text:
A filter device positionable within a blood vessel for trapping blood clots in that vessel, the filter device comprising a head with a plurality of divergent legs each secured at its proximal end, to the head, each leg having a hook arranged at its distal end.
Each leg has a radially outwardly directed radius of curvature to create a conical configuration to the filter assembly, while distributing the stress concentration along the length of the bend, so that the elastic limit of the material, stainless steel in this embodiment, is not exceeded, and which permits compact delivery of the filter, and adequate radially directed force to permit slight hook penetration of a vessel wall.
1. A filter device positionable within a blood vessel, for trapping blood clots, comprising:
an apical head;
a plurality of divergent legs each secured at one of its ends to said head and each having securement means on its distal end with respect to said head;
each of said legs having a first outwardly directed curvature immediately distally adjacent said head, said first curvature in each of said legs allowing insertion of the filter into a small diameter carrier, said first outwardly directed curvature extending in each of said legs, through an arc of about 0.5 inches:
each of said legs having a second outwardly directed curvature in the distalmost portion thereof to provide a slight outwardly directed flare therein while said filter is borne in a carrier, to reduce the possibility of entanglement of the hooks.
2. A filter device as recited in claim 1, wherein said first outwardly directed curvature in each of said legs has a radius of curvature of about 1.4 inches.
3. A filter device as recited in claim 1, wherein said second outwardly directed bend in each of said legs extends through an arc of about 1 inch.
4. A filter device as recited in claim 3, wherein said second outwardly directed bend in each of said legs has a radius of curvature of about 8 inches.
5. A filter device for positioning within a blood vessel, to be utilized for entrapment of blood clots, said filter comprising;
an apical head;
a plurality of divergent legs each secured at one of its ends to said head and each having securement means on its distal end with respect to said head;
each of said legs having a first outwardly directed curvature therein, closely distally adjacent said head, so that the distal remainder of said legs define a generically conical configuration and also to minimize the strain in said legs permitting the filter to be stored in a collapsed state, yet have enough elastic recoil to permit it to expand toward its uncollapsed configuration to allow penetration of a vessel wall upon ejection of the filter therein;
said first outwardly directed bend extending in said legs through an arc of about 0.5 inches;
said first outwardly directed bend having a radius of curvature of about 1.4 inches;
said leg having a second outwardly directed curvature extending through an arc of about 1 inch.
6. A filter device as recited in claim 5, wherein said second outwardly directed curvature has a radius of curvature of about 8 inches.
7. A filter device positionable within a blood vessel for trapping blood clots, comprising:
a apical head;
a plurality of divergent legs each secured at one of its ends to said head and each having securement means on its distal end with respect to said head, said head and said legs having a longitudinally directed center line therewithin;
said head having a cylindrical bore in axial alignment with said center line of said filter adaptable to receive a guidewire for alignment and guidance of said filter upon ejection thereof into a vessel;
said cylindrical bore having a counterbore disposed in each longitudinal end thereof to facilitate emplacement of a guidewire therewith;
said divergent legs having a first radially outwardly directed radius of curvature of about 1.4 inches over an arc of about 0.5 inches in length immediately adjacent said head to permit establishment of a conical geometric configuration to the plurality of legs extending from said apical head.
8. A filter device as recited in claim 7, wherein each of said divergent legs has a second radially outwardly directed radius of curvature of about 8 inches over an arc of about 1 inch in length at the distal end of said each leg, to create a slight outward flare therein, minimizing entanglement thereof.
9. A filter device as recited in claim 7, wherein said divergent legs are made from stainless steel.
This is a division of Ser. No. 07/404,166, filed Sept. 7, 1989, now U.S. Pat. No. 5,059,205.
1. Field of the Invention
This invention relates to implantable blood filters and more particularly to vena cava filters which resist migration once they have been emplaced in a vessel.
2. Prior Art
Blood clots (emboli) carried in the blood stream often constitute serious threats to health and in some instances, to life itself. The reduction of such clots, or their stabilization and arrest of further migration in the circulatory system of the body, are desiderata constantly motivating the development by the medical profession of new techniques and devices for this purpose. Although emboli moving in other portions of the circulatory system can also present serious problems, development of means for preventing emboli from migrating into the pulmonary circulation from the vena cava has received the primary attention.
Ligation of the vena cava was an early technique to minimize movement of emboli therein, with collateral circulation being relied upon to provide adequate venous return of blood to the heart. This procedure, which involved major abdominal surgery, progressed to the utilization of harpstring filters; staple plication; smooth, serrated and channeling external clips evolving into intravascular springs; balloons; and filters. The utilization of filters emplaced in the vascular system provides the obvious advantage over ligation of major blood vessels such as the vena cava, of not requiring general anaesthesia surgery and laparotomy.
U.S. Pat. No. 3,540,431 discloses an intravascular filter for entrapment and arresting of emboli, advanced by Mobin-Uddin and associates. The Mobin-Uddin filter is an umbrella type structure which includes a plurality of expanding struts or ribs which carry points at the divergent ends thereof which impale or engage the vessel wall when the filter is in its expanded state. This device has had problems with migration, and it was withdrawn from the market in 1986.
U.S. Pat. No. 3,952,747 to Kimmell, Jr., incorporated, herein by reference, discloses a vena cava filter as well as a method and apparatus for percutaneous insertion of that filter into a human. The Kimmel disclosure defines the filter as having a plurality of convergent legs disposed in a generally conical array and joined at their convergent ends to an apical hub, each leg having a reversely bent hook at is distal end.
An advancement of the Kimmel, Jr. reference is shown in U.S. Pat. NO. 4,817,600 to Herms et al, also incorporated herein by reference, which discloses a titanium filter having a plurality of legs joined to a head or nose bead, the legs having a first straight portion, and sharply divergent legs extending therefrom.
The present invention features a filter of the Kimmell type having significant improvements to further minimize the likelihood of filter migration and to permit the filter to be emplaced through a small hole and into a vessel. In a first aspect of the invention, the filter of the type mentioned has a head, a plurality of legs attached to the head and divergent leg portions, each leg having securement means on its distal end with respect to the head, the improvement being that the securement means on the distal end of each leg being of multiple curvilinear configuration to define a pad which permits hook engagement of a vessel wall in which the filter is emplaced, while preventing penetration of that hook through the vessel wall, which might otherwise damage body tissue.
In a second or further aspect of the invention, the filter, which in this embodiment preferably is made from stainless steel, has a head with a plurality of legs extending distally therefrom, the head and legs having a centrally disposed longitude axis. The legs have proximal portions which are secured to the head, the proximal portions being generally parallel to the longitudinal axis to the filter. The legs have first portions closely distally adjacent to the head, which have a curvature therein, which geometry allows resilient deformation of the filter into the carrier, and subsequent resilient deformation when expelled from the carrier, so that the filter can end up as a general conical configuration of the legs with respect to the head of the filter. The legs also have a second portion distal to the first portion having a larger radius of curvature so as to permit a slight radial flaring of the hook ends of the legs when the filter is ejected out of its carrier, reducing the possibility of the hooks from becoming entangled with one another, while allowing the legs to be compressed radially inwardly, permitting the filter assembly to be placed into a smaller diameter carrier without stressing the stainless steel material of the legs beyond their elastic limit which would result in the filter having a smaller base diameter upon release from the carrier.
Another aspect of this invention involves the head having a central bore which is arranged co-axially with the longitudinal axis of the filter assembly. The central bore in the head is adapted to receive a guidewire during and after release of the filter assembly from its carrier as an aid for the alignment and centering of the filter assembly within a blood vessel during its implantation.
The first aspect of this invention more particularly involves the arrangement of the distalmost end of each leg defining a pad or landing, and spaced proximally therefrom, there is arranged a hook pointing outwardly from its respective leg in a manner generally normal thereto, and extending further radially outwardly from the longitudinal axis of the filter, than does the pad or landing thereadjacent, to permit the hook to engage the wall of the vessel, yet prevent deep penetration of the wall of the vessel by the hook and leg portions. Each pad or landing on the distalmost end of each leg is comprised of a reverse twisted segment of the wire of the leg, or a segment of the leg welded to the distalmost end and parallel thereto, the segment itself having the hook thereon, extending outwardly radially beyond the radially outwardmost portion of the pad or landing.
The second aspect of this invention more particularly involves the plurality of radially directed curves of each of the legs wherein the first radius of curvature for each leg begins closely distally adjacent the head of the filter, and defines an arc of about 0.5 inches in length with a radius of curvature of about 1.4 inches. The second radius of curvature for each leg extends across an arc about 1 inch in length along the distalmost portion of each leg, with a radius of curvature of about 8.4 inches, each leg being about 2.1 inches in total length. The first radius of curvature provides the generally conical aspect of the legs and head, while allowing delivery of the filter assembly through small holes and distributing the strain throughout the arc of the curve of the leg which is generated when the legs are collapsed into the small opening of the carrier, thus eliminating strains in excess of the yield strain, and the second radius of curvature being sufficient to keep the hooks from entangling with one another when the filter is ejected out its carrier device or during loading thereof, as shown in the aforementioned patent incorporated herewithin.
The objects and advantages of the present invention will become more apparent when viewed in conjunction with the following drawings, in which:
FIG. 1 is a perspective view of a vena cava filter showing the head and legs thereof in one embodiment of this invention;
FIG. 2 is a side elevational view of the distal end of the preferred embodiment of one of the legs of a vena cava filter engaged with the cava wall;
FIG. 3 is a side elevational view of the distal end of a leg of a prior art filter and the cava wall;
FIG. 4 is a side elevational view of a further embodiment of the distal end of a leg of a vena cava filter;
FIG. 5 is a view taken along the lines V--V of FIG. 4;
FIG. 6 is a perspective view of a vena cava filter showing the head and legs thereof of a further embodiment of this invention;
FIG. 7 is a radially inwardly directed view upon one leg and the head of a vena cava filter; and
FIG. 8 is a view taken along the lines VIII--VIII of FIG. 7, showing a further embodiment of the legs of a filter constructed according to the principles of the present invention.
Referring now to the drawings in detail, and particularly to FIG. 1, there is shown a first embodiment of a vena cava filter 10 having an apical hub or head 14 of generally cylindrical shape.
The filter 10 includes a plurality of elongated legs 16 which are of equal length, and are preferably identically configured to each other. The legs 16 are collectively arranged in a generally conical geometric configuration so that the legs 16 converge in the apical head 14, and are symmetrically spaced about a central longitudinally disposed axis "L", which is shown extending through the head 14, in FIG. 1. The legs are of equivalent diameter, being about 0.018 inches in diameter fabricated from stainless steel or titanium wire, and are of about 2.02 inches in final length. In the embodiment of the present invention, six legs are provided, however only one will be described in detail.
At its outermost end 18 which is distal with respect to the apical head 14, each leg 16 has a main portion 20 and a reversely bent portion 22 which is bent through an angle of about 180� in the plane which is tangential to the conical configuration of the legs, and is disposed parallel and contiguous to the main portion 20. A pointed tip portion 24 of the leg which comprises a hook, extends generally radially outwardly, away from the main portion 20 at an angle "A", as shown in FIG. 2 of from 70� to about 90�, preferably 80�; which tip portion 24 is shown piercing a cava wall 26. It is critical that the outwardly extending hook or tip portion 24 extend a greater radial dimension r2 from the center line "L" of the filter 10 that the radial dimension r1, which comprises the radius of the outermost end 18 from the center line "L". The contiguous main and reversibly bent portions 20 and 22 define a pad or landing which is caused to press against the inside of the cava wall 26, after the hook or tip portion 24 has pierced the cava wall 26, preventing penetration of the leg beyond the cava wall 26. This penetration, as shown by a prior art hook 30 in FIG. 3, may cause injury to the patient by movement of the hook 30 outside the cava wall 26. Without the distalmost portion of the leg comprising some form of landing, the hook may penetrate and slide directly through the cava wall. Without the hook or pointed end of the piercing element relatively normal to the wall surface, migration of the filter 10 may result, leading to extreme complications.
A further embodiment of the distal land or pad is shown in FIGS. 4 and 5, wherein a filter leg 40 has an outermost portion 42 comprised of an elongated main portion 44 and an attached segment 46, the distal ends of the attached segment 46 and the main portion 44 having a weld 48 to bind them together and preferably lie generally in the plane tangential to the conical configuration of the legs.
The attached segment 46 has a bent tip portion 50 or hook which is disposed at an angle "B" of about 70� to about 90�, preferably 80� with respect to the filter leg 40, as shown in FIG. 4. It is to be noted that the length of the tip portion 50 is similar to the tip portion 24 shown in FIG. 2, so that the end of the tip portion 50 is radially further from the longitudinal center line of the filter, than is the distalmost end (the weld 48 here) of the outermost portion 42 of the leg 40.
A further embodiment of a vena cava filter 60 is shown in FIG. 6 having an apical head 62, shown more particularly in FIGS. 7 and 8, The filter 60 includes a plurality of elongated legs 64 which are of equal length, and are configured identical to each other. The legs 64 are collectively arranged in a slightly outswept but generally conical configuration so that the legs 64 converge in the head 62, and are symmetrically spaced about a central longitudinally disposed axis "L", which is shown extending through the head 62 in FIG. 1. The legs are about 0.018 inches in diameter fabricated preferably from stainless steel, only one of the legs being described in detail.
Each leg has an outermost or distal end 66 with a hook configuration disposed thereon.
A typical leg 64 is shown further, in FIGS. 7 and 8, each mounted in a bore 68 in the apical head 62, which bore may be parallel to the center line of the filter 60. Each bore 68 receives only about 0.19 inches of the proximalmost end of each leg 64. When all the legs 64 are filling their proper respective bores 68, they are preferably welded therein. Each leg 64, in addition to having a plurality of U-shaped bends 70, disposed in the plane tangential to the cone defined by the legs 64, and intermediate their proximal and distal ends, as recited in the aforementioned incorporated patent, has a first slight bend 72 having a radius of curvature R1 of about 1.4 inches arranged immediately adjacent the apical head 62, to cause the leg(s) 64 to flare radially outwardly about 18 degrees, thus defining their cone shaped configuration, which flare of only one leg 64 is best shown in FIG. 8. This flare permits the filter 60 to have enough elastic recoil to assume its general conical configuration, which is desirable to permit the filtration of blood clots while still allowing blood to flow around the captured clots, thus promoting dissolution of any clot and maintenance of vessel patency. The filter 60 with this flare can be passed through small delivery carriers without exceeding the elastic limit of the stainless steel filter legs 64. This maintenance of the stainless steel legs 64 within their elastic limits is critical to the stress free design, such that the filter 60 can be stored (in its carrier) in a collapsed mode yet have enough of a bend when it has been ejected into a vessel so that there is adequate radially outwardly directed force to permit the hooks to penetrate the caval wall upon the ejection of the filter 60.
A second slight bend 68 having a radius of curvature R2 of about 8.4 inches is disposed along the distal one inch of each leg 64 to provide a very slight, almost unnoticeable flare primarily for utilization in the filter carrier, now shown, so as to keep the hooks biased radially outwardly, and free from entanglement with one another while they are borne in and are ejected from their carrier.
The apical head 62 on the filter 60 has a central cylindrically shaped bore 80 (diam=0.046 inches, length of cylindrical portion 0.075 inches) which is adapted to receive inself aligning engagement, a guidewire (not shown). The bore 80 critically has its cylindrical portion which is in axial alignment with the longitudinal center line "L" of the filter 60. Each end of the bore 80 has a tapered counterbore 82 to permit access of a guidewire into the bore 82. This permits the filter 60 to be aligned and centered along the axis of a guidewire in a vessel during (and after) filter emplacement therein.
Thus there has been shown a vena cava filter having an apical hub from which extends a plurality of configured legs. The legs have a particular hook formation on their distal ends, which provides a landing or pad to prevent the hooks from sliding through the cava wall and injuring the patient thereby. The legs have a further configuration of a pair of outwardly directed curves to primarily create and preserve the general conical shape of the filter after insertion into a vessel through a small delivery hole, and secondarily provide a slight flare in the distal ends of each leg to prevent entanglement of their hooks as they are being moved to their ejection site in a patient.
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text:
Any solution for stupid powermizer
hi all
is there any hack or trick to disable the powermizer
i can't use my love (ubuntu 8.10) because i can't lock or disable the powermizer
my screen flickering after minutes of normal using
i use ubntu 8.10 on my lenovo n200 laptop with the nvidia 7300 Go
nvidia plaese fix the powermizer issue in linux drivers
Re: Any solution for stupid powermizer
I suggest you use the search function of this forum. There are numerous threads regarding your problem.
Re: Any solution for stupid powermizer
For my Lenovo T61, this helps with terminal and open office screen corruption. In /etc/modprobe.d insert the a file "nvidia":
$ cat nvidia
options nvidia NVreg_RegistryDwords="PerfLevelSrc=0x2222"
options nvidia NVreg_Mobile=1
This forces the powermizer feature into a higher performance state.
You *could* try the beta versions of the nvidia 180 driver, but I'm sticking with ones for which there are Ubuntu packages because they are easier to install/uninstall.
none of the changes that people suggest in xorg.conf have any benefit for me.
Re: Any solution for stupid powermizer
thanks pauljohn
your tips working for me in ubuntu 8.04 with 169.12
now it doesn't work for me any more in ubuntu 8.10 and then new 177.XX
yesterday i solved this issue by this thread
i edit my xorg.conf
and add new section
my Xorg become like this
Section "Monitor"
and when i use my laptop at battery power powermizer be at level 0
every things 100% now
sorry for my bad english
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text:
Thanks for redeeming.{{else}}
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{{#if HasMultiPack}} You have {{MultiPackCount}} top spot(s) left. Now loading you into the search listings... {{else}} You have used all top spots. Now loading you into the search listings... {{/if}}{{else}}
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You can now invite anyone to meet at your favorite Starbucks.
Limited-time feature
29 year old man | Elmendorf, TX, USA | Seeking women 24-30 within 100 miles
Southern country gentleman looking for a sweetheart to share the outdoor lifestyle with. :)
I'm a simple guy raised in the outdoors. Some might say I'm a little on the shy side but once you get to know me I like to get out and have a blast doing whatever. I am looking for a best friend to go out with whether it's fishing, hunting, a movie, a few drinks, a nice restaurant, or even just chilling at the house. I would love to take my chances and keep an open mind in hopes to take things from best friend to the next level. No hurry, no worry. Life's too short to forget to stop and enjoy the small things. My idea of the perfect girl is not focused on appearance. I am looking for a strong minded honest woman who knows what she wants in life and isn't afraid to chase it. I want a girl who will teach me some dance moves on Saturday night after I take her out to the lake and spend the day on the boat. I hope you like labs I have a black lab who loves to play in the water and run until he's about to pass out fetching his Frisbee. Family and friends are always important and I look forward to meeting someone who likes to have the occasional weekend BBQ and pool party (drinks optional) and I am always open to meeting a new group of friends. Msg me sometime and don't be afraid to ask anything, kinda hard to tell a life story in a paragraph... This is the first time I've tried the online thing, not sure how this is going to work but cant wait to see what happens...
Camping , Cooking , Dining out , Fishing/Hunting , Hobbies and crafts , Movies/Videos , Exploring new areas , Playing cards , Video games
Billiards / Pool, Bowling, Cycling, Other types of exercise, Running, Walking / Hiking, Weights / Machines
I exercise 3-4 times per week.
I have Dogs
I like Cats, Horses
I have a black lab named Badger who is the best dog a man could ever ask for. I've had other pets like cats and even horses over the years.
Corpus Christi, Choke Canyon, Canyon Lake, I'd like to find plenty more!
Classic Rock and Country Music, Drums and Guitars, Family Guy and Bruce Willis Movies, Spicy food and an occasional mixed drink. The new boat at the coast or the old boat at the private lake, my 4x4 Toyota and my black lab.
Fishing, Hunting, Shooting, Playing with my lab, working on my truck, helping my old man on the ranch, parties with the friends, playing pool, taking the boat out just to cruise, good lord I sound like a redneck....
A hilarious comedy with a title that's probably not allowed on my profile... Gonna have to ask me that one in person :P
Z{{Cta}} {{#if HasMoreInfo}} ?{{CtaSecondary}} {{/if}}
|What he is looking for
|6'0" (182cms)
|5'3" (160cms) to 6'11" (210cms)
|Body type:
|About average
|Slender, About average, A few extra pounds
|Black, Blue, Brown, Grey, Green, Hazel
|Dark blonde
|Auburn / Red, Light brown, Dark brown, Blonde, Dark blonde
|No Way
|No Way, Occasionally, Daily, Cigar aficionado, Yes, but trying to quit
|Social Drinker
|No preference
|Sales / Marketing
|No preference
Currently in sales and administrative position pursuing degree and career in business management and OSHA Safety Certification
|$35,001 to $50,000
|$25,001 to $35,000, $35,001 to $50,000, $50,001 to $75,000, $75,001 to $100,000, $100,001 to $150,000, $150,001+
|No preference
|Have kids:
|Wants kids:
|Definitely, Someday, Not sure
|White / Caucasian
|White / Caucasian
|Christian / Other
|Christian / Catholic, Christian / LDS, Christian / Protestant, Spiritual but not religious, Other, Christian / Other
|Associates degree
|High school
2 Associate's degrees, working toward finishing BBA in addition to TEEX OSHA Safety official certification


text:
Automotive Digital Marketing ProCom
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The Official ADM Professional Community Hash Tag is: #ADMPC
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Filed under: Marketing/Advertising, GM, HyundaiHyundai is the new auto sponsor of the NFL, and will gain access to the league's trademarks for its marketing and advertising access at major events.
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GM out, Hyundai in as NFL audibles auto sponsorship originally appeared on Autoblog on Mon, 29 Jun 2015 14:15:00 EST. Please see our terms for use of feeds.Permalink | Email this | Comments
Filed under: Government/Legal, Green, Marketing/Advertising, TeslaThe first batteries from the Tesla Gigafactory are now expected within 12 months. This is a bit sooner than was previously planned.
Continue reading Economic officials say Tesla gigafactory will open in a year
Economic officials say Tesla gigafactory will open in a year originally appeared on Autoblog on Mon, 29 Jun 2015 12:29:00 EST. Please see our terms for use of feeds.Permalink | Email this | Comments
Filed under: Marketing/Advertising, Alfa Romeo, Chevrolet, Ford, Lotus, NissanWe curate the week's events with a focus on comeback plans for Chevrolet and Alfa Romeo. Plus, other news and notes from the industry.
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Calling Out the Vendor Who Said Links Don't Work for SEO...
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DealerApp Vantage Makes Geo Fencing possible with their Dealer Branded App
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Why Social Trumps Search for Paid Inventory Shopper Traffic
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Posted by Jeff Glackin on June 28, 2015 at 10:30pm 3 Comments 6 Likes
It's no secret I have never been a huge fan of PPC or Google Adwords. Don't get me wrong, I feel they have their place but what I have typically struggled with is the lack of transparency in this area of digital marketing. Dealerships have blindly set budgets not even knowing the fees being charged by their vendor or the true results of the campaigns placed on their behalf.
After reading this post on the Moz blog, it just dumped fuel on my fire. I recently heard Gary Vaynerchuk call Google Adwords traditional advertising. I love that guy! He recently just shifted two million dollars from Google to Facebook. I am seeing dealerships start to make that same shift. Here's…Continue
Posted by Big Tom LaPointe on June 28, 2015 at 3:00am 0 Comments 0 Likes
It sounds simple enough, but are you sure your dealership live chat appears on mobile devices? More and more I talk to dealers who say they are happy with their chat, yet their chat icons do not appear on their shoppers' mobile devices. And often when they do, the chat windows are the same ones served on desktop computers, so they are oversized and typically extend off the screen.
I understand that website chat is a small part of the marketing picture for dealers, but a high-performing chat can generate as much a fifty percent increase in website contact lead forms, so ensuring it also operates efficiently on mobile devices is critical, with half or more of unique website visits coming in the form of…Continue
Posted by Paul Potratz on June 26, 2015 at 10:57am 0 Comments 0 Likes
Breaking routines isn't easy but change yields long term results. On this week's Hard Facts, Samantha shows you how to shake up your routine and your priorities.
Posted by Bradley Paschal on June 26, 2015 at 5:00pm 0 Comments 1 Like
Amarillo, Texas – Street Volkswagen of Amarillo will move to its new and permanent facility at 8707 Pilgrim Drive the last weekend in June. The dealership has been running business at their temporary location at 2725 S.W. 45th Avenue since August of 2013.
Street Volkswagen of Amarillo will move at the end of June from its temporary location to its new state of the art facility on the 5000 block of Soncy Road. The store will be open by July 1 serving Amarillo as a full service dealership with automotive sales, service and parts departments.
The project idea for the new store…Continue
Posted by Big Tom LaPointe on June 25, 2015 at 8:00am 0 Comments 1 Like
I recently stayed with a millennial friend who is enjoying her summer break from college by watching YouTube sitcoms until 3 am and shopping for shoes online. A business friend of mine was at the airport last week waiting for his 7 am flight and surfing the web for an Apple watch and looking for Taylor Swift tickets for his daughter. In either of these cases, the shopping could have easily been for a car, and THAT is why you definitely want 24/7 live chat on your dealership website.
During regular business hours, do you ONLY greet shoppers on the lot during certain hours? Well, the internet is open 24 hours a day, and so is your website, so it only makes sense to have a live person greet them when they arrive. Just like you never know…Continue
Posted by Richard Holland on June 25, 2015 at 6:00am 0 Comments 1 Like
The service department tends to be the busiest place in a dealership, and service managers must stay in tune with what's going on. While meetings and discussions can be useful, at times they only result in vague ideas the service staff never acts upon. Just like in any organization, a service department is only as good as its leader. Sometimes, you have to get in the trenches to really understand employee problems, obstacles, and frustrations.
To get on the employees' level, service department managers may find it helpful to visit with their employees in an active and participatory manner, one-on-one. I'm not talking about individual meetings. Rather, I mean managers should shadow employees in areas integral to efficient operations. Service managers can learn…Continue
Posted by Mike Gorun on June 24, 2015 at 6:00am 2 Comments 1 Like
If you were to ask today's consumers if they'd like to hang out at a car dealership, chances are that the majority would respond "no." When consumers do visit a dealership to purchase a vehicle or get their vehicle serviced, many times the process can be longer than desired and is not always a great experience for the consumer. Dealerships have been attempting to streamline the sales and service process through the use of technology to make the entire process faster and more efficient so as to be more consumer friendly.
Some dealerships are going a little bit further to make the customer experience more enjoyable with the addition of delis, Starbucks, movie theaters and hair salons, as permanent fixtures. And thinking even further outside the box, a recent Automotive…Continue
Posted by Willis Williams on June 23, 2015 at 6:25am 0 Comments 3 Likes
Are you one of the few that blasts Social Media as a form of marketing? Maybe you just don't believe that it works. Maybe you think it's a huge waste of time. Well the good news is that you're not alone. The bad news is that the numbers of non-believers are rapidly dwindling.
Let's say that you're on the fence about whether there's actual ROI (return on investment) behind managing a social media page. I'm speaking on either budget or time as your ROI measurement. You may be asking yourself "Is this worth it?" Everybody seems to be doing it but does it mean you have to? I can assure you that a social media strategy not only works but it's actually good for your dealership.
When it comes to running a dealership, there is basically one goal: to sell units. Of course, advertising and…Continue
Posted by J.D. Rucker on June 23, 2015 at 2:00am 0 Comments 3 Likes
I've been pretty torn over the last few months. On one hand, I'm so pleased to see that dealers (and even some vendors) are really starting to embrace building content pages on their website. On the other hand, I'm concerned that many companies are starting to promote building these pages as their complete SEO strategy. What's worse is that many dealers are starting to believe them.
We came across this recently when a dealer wanted to find out whether our SEO services were having a positive effect on their traffic, leads, and sales, or if it was another company that was working on things simultaneously. The other company builds pages. That's it. They don't support these pages with other signals and they don't build the pages with increased sales in mind.
2012 was the last time I…Continue
Posted by Dana Detrick-Clark on June 21, 2015 at 10:00am 1 Comment 1 Like
It's a timeless story: a dad watches his little girl grow into an independent young woman. But no matter how many times a major auto maker tells it, we still can't help but grab the tissues to wipe our tears while we hit "share" on social media.
But how does making us cry make us buy? In essence, they do a phenomenal job of taking a feature (in this case, safety), and turning it into a more specific benefit ("My child will be protected as she goes into the world without me"). They construct a relatable, emotional story that we can easily apply to our own lives, which in turn, allows us to see ourselves behind their wheel.…Continue
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New gene emergence is so far assumed to be mostly driven by duplication and divergence of existing genes. The possibility that entirely new genes could emerge out of the non-coding genomic background was long thought to be almost negligible. With the increasing availability of fully sequenced genomes across broad scales of phylogeny, it has become possible to systematically study the origin of new genes over time and thus revisit this question.
We have used phylostratigraphy to assess trends of gene evolution across successive phylogenetic phases, using mostly the well-annotated mouse genome as a reference. We find several significant general trends and confirm them for three other vertebrate genomes (humans, zebrafish and stickleback). Younger genes are shorter, both with respect to gene length, as well as to open reading frame length. They contain also fewer exons and have fewer recognizable domains. Average exon length, on the other hand, does not change much over time. Only the most recently evolved genes have longer exons and they are often associated with active promotor regions, i.e. are part of bidirectional promotors. We have also revisited the possibility that de novo evolution of genes could occur even within existing genes, by making use of an alternative reading frame (overprinting). We find several cases among the annotated Ensembl ORFs, where the new reading frame has emerged at a higher phylostratigraphic level than the original one. We discuss some of these overprinted genes, which include also the Hoxa9 gene where an alternative reading frame covering the homeobox has emerged within the lineage leading to rodents and primates (Euarchontoglires).
We suggest that the overall trends of gene emergence are more compatible with a de novo evolution model for orphan genes than a general duplication-divergence model. Hence de novo evolution of genes appears to have occurred continuously throughout evolutionary time and should therefore be considered as a general mechanism for the emergence of new gene functions.
The hallmark of the signature of a new gene (or orphan gene) is that it arises at some time within the evolutionary lineage towards an extant organism and has no similarity with genes in organisms that have split before this time [1-3]. This distinguishes orphan genes from genes that arise through full or partial duplication processes to form paralogous genes or gene families [4,5]. It has been proposed that orphan genes are likely to play a major role in lineage specific adaptations [1-3,6] and thus contribute to evolutionary innovations. There are two major models of how orphan genes can arise [3]. The first is the duplication-divergence model, which assumes that they emerge through an initial duplication of other genes, but this is followed by rapid divergence, such that all similarity to the parent gene is lost [1]. The alternative is the de novo evolution model, which assumes that genes can directly arise out of non-coding DNA [7]. Although this second possibility seemed initially rather unlikely, such genes have been found in Drosophila[8-10], yeast [11,12], mouse [13], Plasmodium [14] plants [15] and humans [16-18]. In fact, there is now increasing evidence that de novo evolution may be rather frequent. Studies in yeast have suggested that a large number of transcripts without annotation are actively transcribed and translated [19,20] and that such transcripts could be a source for de novo gene emergence (called "proto-genes") [7,20].
We have developed phylostratigraphy as a method that identifies the genes that have arisen at each stage of a series of phylogenetically relevant splitting events [21]. This allows to systematically study the characteristics of such genes over time [22-25]. Using this approach we found that gene emergence rates are particularly high in the youngest lineages, implying a very active process of de novo evolution, since the times considered for these youngest lineages are too short for the duplication-divergence model to apply [3]. This is in agreement with the proto-gene concept, where non-coding transcripts are considered as possible sources of new genes [19,20]. However, a study of emergence trends across the whole phylogeny is still missing.
In the present paper we use the mouse as a focal species, which has a particularly well annotated genome. We show that it is indeed possible to derive distinctive patterns for gene emergence, which appear to be generally in accordance with a de novo evolution model. As a special case of de novo evolution, we revisit the possibility that existing genes have developed an independent second reading frame. Evolution of new genes within such double reading frame arrangements have been known since some time [26,27] (called "overprinting" by [27]). They have been well studied in viruses [28,29], but several examples are also known from eukaryotes and have been studied in detail for some genes [30-32]. Chung et al. [33] provided a first systematic approach to identify such alternative reading frames (ARFs) in mammals and suggested 40 candidate genes which appeared to use ARFs. We find here that it is indeed possible to retrieve even among annotated genes additional cases of overprinting, where the alternative reading frame maps to a different phylostratum than the original reading frame. This suggests that existing genes may readily become templates for de novo evolution of new gene functions within them, further supporting the notion that de novo evolution of gene functions are possible.
The duplication-divergence versus the de novo evolution model for orphan gene emergence make some different predictions with respect to gene emergence over time, for example on length distributions and exon distributions, as detailed below. Apart of looking for such differential predictions, it is also of interest to assess general patterns, such as orphan gene distribution across the genome, as well as the emergence of associated promotors. Below, we describe first how we assign the genes to different age classes and then use this assignment to study gene emergence trends and patterns.
Phylostratigraphy of mouse genes
The phylostratigraphic approach was used to estimate the time of emergence of each of 20,775 annotated protein coding loci in the mouse genome (Figure 1). Twenty phylogenetic classes or phylostrata were defined according to consensus phylogenetic relationships between groups with enough available protein sequence information. The first phylostratum (ps1) represents the basis of all cellular life, i.e. the oldest genes, while the last phylostratum (ps20) represents the lineage leading to mouse since the split from rat blastp was used to assign for each mouse gene its presumptive origin within this phylostratigraphy. For this we use an e-value cutoff of < 10-3, which has previously been found to provide an optimal compromise between sensitivity and accuracy [1,34]. The results of the assignment to the respective phylostrata are listed in Additional file 1: Table S1 and summarized in Figure 1.
Figure 1. Phylostratigraphy of the mouse genome. Each phylostratum corresponds to a node in the phylogenetic tree of the species. Representative outgroups are named under each node. The bar graph to the right represents the number of annotated protein-coding genes mapped to the respective phylostratum at a blastp threshold of e < 10-3.
Additional file 1: Table S1. Excel workbook with compilation of all loci from mouse, humans, zebrafish and stickleback assigned to their respective phylostrata.
Format: XLSX Size: 2.1MB Download file
Approximately 60% of the annotated protein coding genes in the mouse genome originate from prokaryotic and basal eukaryotic ancestors (ps1-2). The rest of the genes have emerged later in the phylogenetic history, with peaks correlating to large scale biological transitions. For example, the peak around ps6 represents the single-cell to multicellular organism transition [23] and the peak around ps11-12 represents the invertebrate to vertebrate transition. Another peak is evident at ps20, representing all genes that have evolved since the rat/mouse split. Although this may partly be ascribed to annotation problems within the youngest group of genes [7] many of them are likely to represent de novo evolved genes, since mouse and rat are so close to each other that any duplicated gene would easily be traceable, even if it would evolve with the rate of a non-functional pseudogene.
Genomic features across ages
We used the phylostratigraphic assignment of the genes to assess the emergence trends over time for several relevant gene features (Figure 2). Some of the gene features were selected to allow to distinguish the duplication-divergence model from the de novo model.
Figure 2. Features of genes for different phylogenetic age groups in the mouse. A. Gene length distributions (includes exons and introns); B. ORF length distributions; C. Median number of InterPro domains per gene; D. Median exon numbers per gene; E. Median exon lengths per gene. Box-whisker plots around median values (bars) with quartile ranges and outliers as dots. Significant (p < 0.01) distribution differences were found for ps20 (marked with *) in E (t-test). Gray bars indicate phylostrata with non-randomly distributed values for each variable, based on permutations (n = 10,000) and Kolmogorov-Smirnov tests (p<0.01).
With respect to gene length, the de novo model would predict that younger genes should be shorter than older genes, since it is unlikely that complex protein sequences emerge de novo. Rather one would expect that they could increase in size over evolutionary time. In the duplication-divergence model one would not expect length-dependence over time, since long and short genes should be equally likely subject to duplication at any time level. The results show, however, a strong length-dependence over time, both with respect to gene length (Figure 2A) as well as open reading frame length (Figure 2B). The Spearman rank correlations across the 20 phylostrata are very high (Table 1) suggesting an almost continuous trend over time. Such trends for gene length distributions had also previously been noted in analyses using fewer age classes [35,36].
Table 1. List of overprinted genes detected via a phylostratigraphic approach based on annotated ORFs in Ensembl
A differential prediction can also be made for the expected correlation with protein domain emergence. De novo evolved proteins will initially have no domains which are shared with other genes, while duplicated genes would tend to retain domains of their parental genes [37]. Hence, the de novo evolution would predict domain gain over time, while no distinct pattern is expected for the duplication-divergence model. Again we find indeed a strong time-dependence with a continuous trend for domain emergence (Figure 2C; Table 1), supporting the de novo model.
De novo emerged genes should also have initially fewer exons, but could be expected to accumulate additional ones over time. In the duplication-divergence model, on the other hand, one would not expect a time dependency of exon numbers, since this mechanism should work the same at every time horizon. However, we find a strong trend of exon gain over time (Figure 2D; Table 1), supporting the de novo model.
Average exon length, on the other hand, shows no clear age-dependence (Figure 2E). Only the youngest genes (ps20) have significantly longer exons (Figure 2E) suggesting a fast secondary acquisition of introns after gene emergence, or gene fusion effects [38].
To assess whether these patterns constitute general trends that can be observed in other lineages as well, we have also analyzed them for humans, stickleback and zebrafish lineages. Humans were included since the genome is equally well annotated as the mouse genome, the fish species represent another vertebrate lineage split more than 400 million years ago. Analysis of these three genomes confirms indeed almost all trends with similarly high correlation coefficients (Figure 3; Table 1). Gene length, ORF length, domain numbers and exon numbers show all a clear time-dependence. Only one comparison, namely the significantly longer exons in the youngest genes was not confirmed for the two fish genomes. However, for these genomes this may in part be due to a bias against annotating genes that have no homologs in other genomes. Note that the shared trends can only partly be ascribed to the shared early history of vertebrates. The fish versus mammal lineages have had 800 million years of independent evolution, during which the trends seen in the genes shared between the lineages could have been subject to changes, unless they were robust.
Figure 3. Trend comparisons in additional genomes. Same analysis as shown in Figure 2, but for humans (Homo sapiens), stickleback (Gasterosteus aculeatus) and zebrafish (Danio rerio). Note that the fish phylostratigraphy has only 14 phylostrata in total so far, whereby ps1-12 are shared with the mammal genomes. Statistical annotations as in Figure 2.
Chromosomal distribution
Gene emergence appears to be randomly scattered across all chromosomes (Kolmogorov-Smirnov test, 10,000 permutations), with exception of a few clusters (Figure 4A). However, most of these represent a single locally expanded gene family, with one interesting exception on chromosome 14. This is a block of about 5 Mb located at the centromeric end of the chromosome (Figure 4B). This cluster has already been described as a complex region including a gene family involved in regulating synaptic activity in mouse [39]. Our analysis suggests that it is indeed a region with a high rate of gene birth, composed of sets of genes that have arisen at different times. But, apart of this special region, there is currently no indication for a localized generation of new genes. Hence, although the de novo and the duplication-divergence model are both compatible with this pattern, one could have expected for a duplication model that more local clusters could have become apparent.
Figure 4. Circos plots of chromosomes and phylogenetic age of their genes. Clockwise orientation, tick marks every 10 Mb. Genes become younger towards the outer part of the circle (represented by hues of red to blue). A. Whole genome representation. B. Chromosome 14. Green mark indicates a local cluster of young genes spanning several phylostrata.
Association with transcriptionally active sites
Transcriptionally active regions can be identified by specific marks, such as CpG islands, histone methylation (H3K4me3) peaks or DNAseI sensitivity hotspots. We find that genes in ps1-3 (representing origin of cellular organisms, eukaryotes and opisthokonts, respectively) have a significant excess of genes associated with these regions (Figure 5A), in line with their predominantly general cellular functions. Another over-representation peak occurs at ps8 (evolution of chordates), which is of yet unclear significance.
Figure 5. Association of transcription marks by phylostratum. Log-odds of gene counts as enrichment. A) combination of three transcriptional hallmarks: CpG islands, H3K4me3 peaks and DNAseI sensitivity hotspots. B) to D) profiles for single transcription marks, separately for unidirectional promotors (black lines) and bidirectional promotors (red lines). B) CpG islands, C) H3K4me3 peaks, D) DNAseI sensitivity hotspots. * Hypergeometric test, FDR corrected, p<0.01.
With respect to the de novo model, it is particularly interesting to ask whether the most recently evolved genes are associated with such marks, since this could imply that they tend to make use of existing promotors upon their emergence. We find indeed a significant over-representation of transcriptional marks for genes that have emerged in ps20 (Figure 5A). This would suggest that the transcription of de novo evolved genes is initially often dependent on the proximity to an existing transcriptionally active region. Intriguingly, however, the ps19 genes show a significant under-representation with respect to the association of these three marks. This would suggest that new genes acquire rather quickly own regulatory elements, independent of the standard marks.
To explore this pattern further, we analyzed each of the three marks separately and further distinguished between unidirectional and bidirectional promotors (Figure 5B-C). The latter are the most evident candidates of cases where newly evolved genes take advantage of an existing regulatory region. We find that bidirectional promotors are indeed consistently over-represented in genes from ps20 for all three marks.
Testis expressed genes
Testis is known to have the largest number of tissue-specifically expressed genes, many of which are newly evolved genes [5]. It has therefore been suggested that new genes arise predominantly first in the context of testis expression, before acquiring roles in other tissues - the "out of testis hypothesis" [5].
When plotting the over- and under-representation profiles specifically for testis expressed genes, we find a significant enrichment for testis genes mostly from ps15 onwards (Figure 6). But there is no significant peak at ps20 as one would have expected under the "out of testis" hypothesis. On the other hand, it should be noted that we are looking here at protein-coding genes only, while many newly emerged testis expressed genes may initially have been non-coding and have evolved a functional ORF only later on [3]. This hypothesis is in line with the peak seen in ps19, which represents the time frame within which functional ORFs could have evolved.
Figure 6. Phylogenetic profile of genes expressed in mouse testes. Log-odds of expressed genes as enrichment for each phylostratum. * Hypergeometric test, Bonferroni corrected, p<0.01.
Alternative reading frames
De novo evolution of genes could also occur within the context of an existing gene, for example through the emergence of an alternative exon that changes the reading frame or by making use of a different start codon which would lead to the translation of an alternative reading frame [26,27]. We used the phylostratigraphy approach to assess the age of the ORFs of genes with two annotated reading frames and find that they can indeed be significantly different, indicating a secondary evolution of a new gene within an existing gene. We can find 13 such genes among the current Ensembl annotated reading frames, only two of which were previously identified as overprinted genes (Table 2). We discuss here three further examples representing three general patterns (Figure 7).
Figure 7. Examples for overprinting of genes. Gene structures of four genes are shown, whereby the exons (boxes) are drawn to scale, while the introns (lines) are not to scale. Open boxes are non-coding, filled boxes represent the reading frames. Ancestral gene versions are yellow, derived ones are purple. The Figure is based on annotations and graphics from Ensembl, whereby only the relevant splice variants are shown. A: Reep6 (ENSMUST00000030237 and ENSMUST00000060501); B: Polr1d (ENSMUST00000154641 and ENSMUST00000114425); C: Hoxa9 (ENSMUST00000048680, ENSMUST00000110557 and ENSMUST00000050970).
The first example is the gene Reep6, where an additional start codon has evolved in the first exon, which initiates a new reading frame, overlapping the ancestral one (Figure 7A). The older product of Reep6 maps to ps2, the newer one to ps17, i.e. it appears to have acquired a new function at the boreoeutherian divergence. Interestingly, when looking at the gene trees of these proteins, one can see a clear acceleration of divergence rates in conjunction with the emergence of the second reading frame for Reep6, but not for its nearest paralog Reep5, which has not developed the second reading frame (Figure 8). Such acceleration is a hallmark of an adaptive phase and was also found in viruses [29].
Figure 8. Phylogenetic tree for Reep5 (blue labels) and Reep6 (red/black labels). Both genes are present in euteleostomes (ps12), and belong to a larger family of eukaryotic genes (ps2). The Reep6 locus in mouse codes for two proteins of different age. The older protein (Reep6) was mapped to ps2 (eukaryotes), the newer protein (Reep6 overprint) to ps17 (boreoeutherians). Note the enhanced substitution rate at the basis of this subtree (in black), as represented by branch length. Modified gene tree from Ensembl record ENSGT00550000074535.
The second example for overprinting is Polr1d, a subunit of RNA polymerase I and III, which has acquired two additional exons at the end of the ancestral gene. Alternative splicing leads thus to a new protein that shares only the start codon and a few initial amino acids with the ancestral gene (Figure 7B). The ancestral protein maps to ps2, the derived one to ps5, i.e. this arrangement with two protein products from the same gene region is highly conserved.
The third example is Hoxa9, one of the canonical Hox genes involved in anterior-posterior patterning. In this case, the ancestral gene has first acquired an additional intron that leads to a truncated version of a protein, an arrangement that is conserved between birds to mammals [40] (ps14). On top of this, an additional 5′-exon, driven by a new promotor, has evolved within the Euarchontoglires (ps18). This splices to the acceptor of the new intron and creates thus a new reading frame (Figure 7C). Interestingly, this reading frame covers the homeobox and is conserved between primates and rodents.
The trends described above provide new insights into the modes of gene emergence over time. For the two models, de novo evolution versus duplication-divergence, it seems that de novo evolution is better compatible with these trends. But before coming to the interpretations, we should first like to discuss the technical aspects of our approach.
We rely generally on blastp searches for classifying the genes to phylostrata. There have been extensive simulation efforts that have shown that this is an adequate procedure [34]. However, if one would add manual curation, including the use of a combination of different search algorithms, one would indeed classify a number of genes to older phylostrata. On the other hand, we are focusing here on general trends, not on absolute numbers. Given that most of these trends are robust, both with respect to statistical testing, as well as for confirming them for the much less well annotated fish genomes, we consider the possible misclassification problem as small.
We relate our analysis only to the currently annotated Ensembl reading frames, although these are in a constant flux, due to curation and further refinement of annotation procedures. In fact, it has already been noted that the currently available annotations underestimate the number of orphan genes, since finding a homologue for a gene is one accessory criterion for annotation. This affects mostly the genes from ps20, which are under-represented [3,9], although they are the best candidates for ongoing de novo evolution. Hence, although some noise is expected in the data and the assignment fidelity, it would be very unlikely that a systematic artifact causes the trends observed.
De novo evolution versus duplication-divergence
The de novo emergence of a gene out of non-coding DNA requires only some form of transcription, as well as simple signals that define its start and its end and possibly splice sites, as well as some open reading frame [3,7]. Since all of these signals are rather short, they are expected to occur frequently even in random sequences. Genes emerging from such random combination of signals have been called proto-genes [7,20] and analysis of ribosome association profiles in yeast has suggested that they are abundantly translated [19,20]. Accordingly, they could easily serve as a continuous source of short genes that are ready to become recruited to functional pathways and can then become more complex over time. Hence, new genes that arise according to this model would initially be short, have few introns and domains and would often be associated with existing regulatory elements. These are indeed the overall trends that we observe.
The duplication-divergence model, on the other hand, seems much less compatible with these trends. Under this model, one would expect that the new gene should inherit the gene structure from the parental gene. Since long and short genes should equally often be the source of new genes, and since duplications should happen similarly at all time horizons, one would not expect to see the dependence between age and length features.
Domain number is also highly correlated with age, with younger genes having far fewer domains. This is not a simple effect of the similarity searches that we have used, since the domain annotation in Interpro is based on a combination of a variety of different procedures that go beyond blastp matches [41]. Hence, this observation confirms that not only new genes, but also new domains can arise over time [42,43]. On the other hand, only half of the genes contain known domains [37], i.e. having a domain is not a prerequisite of protein function. In fact, many proteins are known to be intrinsically unstructured [44-46].
Regulatory evolution
It is still unclear how a new gene can acquire its regulatory elements. One possibility is that there are many cryptic transcriptional initiation sites around the genome. Indeed, it appears that most of the genome becomes transcribed at some time [47,48]. However, much of this may be co-transcription or spurious initiation. Moreover, to allow a transcript to become functional (i.e. to become subject to positive selection), it requires some form of stable and heritable regulation. We have therefore evaluated the possibility that new genes make use of existing promotors. It is known that RNA polymerase II promotors have a general tendency for divergent transcription within the nucleosome-free region associated with most promotors [49,50]. We find indeed an enrichment of general signatures of active promotors in association with the most recently evolved genes (ps20). This is mostly due to bidirectional promotors, where the general tendency of RNA PolII for bidirectional transcription may have become extended to form a new transcript. Intriguingly, the next phylostratum (ps19) shows an under-representation of genes among bidirectional promotors, which would suggest that a new gene that has become functional could rather quickly gain its own independent promotor elements.
Another way of making use of an existing promotor is to develop an alternative reading frame within an existing gene. This can be caused by the acquisition of an alternative splicing, whereby the original start codon is retained (e.g. in Polr1d). Alternatively, a separate start codon becomes used that initiates a different reading frame (e.g. Reep6). This has long been thought to be very unlikely, mostly because of the common notion that in eukaryotes only the first AUG serves as a start codon in a mRNA. However, polycistronic mRNAs are known to occur in eukaryotes as well [51], i.e. the use of additional start codons from the same transcript is not without precedence. The third possibility to initiate an alternative reading frame within an existing gene is a new upstream exon, driven by a new promotor, combined with alternative splicing. This has apparently happened in the case of the Hoxa9 gene. This is also the mechanism that was found for the previously well-studied example of overprinting in the Cdkn2a gene [32]. This raises of course the question of how the new promotor for the new upstream exon has evolved. However, it has been shown that there is a widespread presence of long-range regulatory activities in the mouse genome, which can act on inserted promotors [52]. Thus, it seems indeed rather conceivable that random mutations in such potentially active regions might suffice to create a new regulated initiation site.
We expect that it should be possible to detect many more cases of overprinting, if one does not only search annotated reading frames, as we have done here. For example, Chung et al. [33] have identified 40 candidates for overprinting in humans using a probabilistic search strategy. With the much better genome sampling that we have nowadays, it should be possible to refine the searches even further.
Our search has specifically focused on cases where the overprinted reading frame has emerged later than the original one. Two of the previously well-studied genes fall into this class and we have recovered them. Such secondarily evolved proteins are the ones that give the strongest support for a de novo evolution mechanism, since alternative reading frames of long existing genes can be considered as almost random sequences. Hence, the fact that new proteins can arise out of them is a strong argument for the reality of de novo evolution [26,27,33].
The phylostratigraphy-based analysis of trends associated with gene emergence in the mouse genome is well compatible with a frequent de novo emergence of orphan genes. This seems to be in contrast to previous assessments, which found only a small fraction of cases of de novo evolution [10,53,54]. However, it is necessary to emphasize that this depends very much on the criteria that were used. These early studies were still constrained by the assumption that de novo evolution must be rare and the criteria were therefore tuned to be very restrictive to be sure that only the best-supported cases were included. In addition, it has initially been unclear whether any new gene that includes part of a transposable element should be classified in a separate class [53], since strictly speaking it contains at least partly a duplicated sequence. On the other hand, if the transposable element fragment does not contribute its reading frame to the new gene, we would now consider it as a de novo gene, given that we find also overprinting in other existing genes. We should also reiterate that our analysis here is strictly based on genes that were annotated as protein coding, whereby the criteria for annotation of genes are still rather restrictive and tend not to consider short open reading frames, although these may be functional as well [51]. Further, all non-coding RNAs are still excluded from this analysis, although the emergence of new de novo genes may be characterized by a phase where it acts as non-coding RNA first [11,13]. Hence, we conclude that we are only at the beginning to understand the true impact of de novo gene evolution on shaping the genome and emergence of new gene functions.
The phylostratigraphic procedure [21] is a blastp-based sorting of all protein sequences of an organism according to their phylogenetic emergence. The procedure uses the annotated genes of the focal organism and compares them to all available annotated and non-annotated genome data to infer the first time of emergence of a given gene. Accordingly, all available proteins from protein coding loci in the version 66 of Ensembl [55] for Mus musculus (obtained through BioMart [56]) were queried against the nr database from NCBI using an e-value threshold of < 10-3, which has been shown to be optimal for such an analysis [1,34]. For phylostratum 12, given the low number of protein sequences for outgroups (Cyclostomata/Chondrichthyes), EST and Trace data were included in a tblastn query (translated nucleotide comparison), using an e-value threshold of <10-15. The computation of the phylostratigraphic maps was performed on the Phylostrat server of the IRB Institute, Zagreb, Croatia. Twenty phylogenetic age classes, i.e. phylostrata, were defined based on consensus phylogenetic relationships (Figure 1). The age of a locus was assigned taking into account the oldest detectable similarity of any of its protein products. This approach is targeted to the detection of orphan genes, as it neglects events of exon shuffling or gene fusion as genomic novelties.
Gene structure analyses
Structural gene features were obtained from version 66 of Ensembl through BioMart for mouse (Mus musculus), and from version 68 for human (Homo sapiens), zebrafish (Danio rerio) and stickleback (Gasterosteus aculeatus). Domain information from Interpro [41] was also obtained through BioMart, and the number of different entries per gene was used as a proxy to the number of domains. Phylostratigraphic analyses were tested with hypergeometric statistics for discrete features and correlations were calculated for continuous features. A combination of permutations (n=10,000) and Kolmogorov-Smirnov tests was used to assess the significance of each phylostratum per variable. Kolmogorov-Smirnov tests were also applied to distance distributions. Other statistical tests were perfomed using R version 2.15.1 [57] and PASW version 18.0.0 [58]. Circular plots for the mouse genome were done with Circos [59].
Transcription associated regions
Regions of high transcriptional activity from basal promotors were defined as those containing any of these three features: presence of CpG islands, H3K4me3 peaks or DNAseI sensitivity hotspots. These features allow broad range recognition of potential and actual sites with enhanced transcriptional activity. All datasets were taken from the UCSC Genome Browser [60,61] through the Table Browser tool [62]. Datasets for H3K4me3 ChIP-seq (Mouse ENCODE Consortium, 2012) were obtained from the available tracks from Histone Modification by ChIp-seq at ENCODE/LICR (Ludwig Institute for Cancer Research). Available tissue data at the time of the study include bone marrow, cortex, cerebellum, heart, kidney, liver, lung, mouse embryonic fibroblasts and spleen (all from 8 week old mice). Only peak data were used. Datasets for DNAseI sensitivity assays were obtained from the DNAseI Hypersensitivity by Digital DNAseI from ENCODE/University of Washington tracks [63]. Only hotspots information was used and only tracks corresponding to C57BL/6 mice. Genes were considered to be associated to these marks if the transcription start site was found at a distance of 1,250 bases or less from the mark, accounting for potential offsets in annotations and allowing the assumption that transcriptional activity might affect more drastically those regions in a short range. Analyses of overlap between regions were performed with the BEDtools suite [64]. Phylostratigraphic enrichment was calculated as log-odds and tested using hypergeometric statistics and FDR correction.
Expression data for testis
Mouse microarray expression data from [65] were obtained from the authors' website (http://hugheslab.ccbr.utoronto.ca/supplementary-data/Zhang/ webcite). This study was selected because of the wide spectrum of tissues considered, which allow for an unbiased measure of expression for a large set of genes. Given that the study was performed using a draft of the mouse genome, the probes were re-annotated using Blat [66] to match the phylostratigraphic map of the mouse. Ambiguous and poorly matching probes were discarded from the analyses.
Secondary reading frames
This screen was devised to find annotated candidates for emergence of new genes within existing genes based on annotated products. All complete open reading frames corresponding to the same genomic location (ENSMUSG) were considered as candidates, if the minimum and maximum age values differed by at least 2 phylostrata (to avoid screening borderline classifications between phylostrata). Within each genomic location, ORFs were aligned at the nucleotide and protein level using global (needle) [67] and local alignments (blastn and blastp, database size adjusted to emulate nr-sized searches) [68]. The oldest product was used as reference, and any products with younger phylostrata values were used as query. In the case of multiple older products, comparisons were made against all possible products from the oldest phylostratum. Non-matching protein alignments coming from matching nucleotide alignments were considered as genes with alternative reading frames. These were screened manually in Geneious (version 5.6.5) to identify conservation patterns of start and stop codons in other species. Additionally, using the Compara platform from Ensembl [69], phylogenetic trees for selected candidates were analyzed.
Competing interests
The authors declare that they have no competing interest.
Authors' contributions
RN retrieved the data and performed the analyses. RN and DT conceived the study, interpreted the data and wrote the manuscript. All authors read and approved the final manuscript.
We thank Tomislav Domazet-Lošo for providing access to the Phylostrat server at the IRB in Zagreb, Croatia; Robert Bakaric for development and support of the Phylostrat server and Sebastian Meyer for work on preliminary tests regarding mouse overprinting. RN is member of the International Max-Planck Research School (IMPRS) for Evolutionary Biology.
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