With hundreds of tissue donors, it is the most extensive guide ever created; could lead to better diagnosis, treatment of diseases associated with ‘bad luck or bad habits’
Researchers have created the largest atlas of genome mutations after fertilization in healthy human tissue ever assembled — a scientific advancement that could unlock new avenues for diagnosing and treating genetic disease. It is the largest ever in terms of the combined number of tissues and number of donors sampled.
The development points the way toward understanding the genetic underpinnings of disease associated with cancer, as well as innumerable conditions caused by cellular malfunction, including aging. The atlas could be useful in diagnosing medical conditions and potentially useful in reversing genetic mutations that cause disease.
“If you’re talking about genetic changes being the basis of disease, there are a wide variety of technologies now that allow us to make changes to the genome,” said senior author Don Conrad, Ph.D., associate professor and chief of the Division of Genetics at OHSU’s Oregon National Primate Research Center. “It may be possible to change those mutations we’ve acquired due to bad luck or bad habits, and change them back to what they were before.”
Window into cell mutations
Researchers generated the atlas using 54 tissue and cell types compiled after death from 948 individuals who donated their bodies for the National Institute of Health’s Genotype-Tissue Expression Program.
Every person begins as a single cell at the moment of conception, carrying a DNA blueprint within the nucleus of that first fertilized cell. Using those original DNA instructions, the cell divides and replicates into vast groups of cells that form distinct tissues carrying out unique functions in the body. At any one time, the average person comprises about 30 trillion cells; in the course of a lifetime, that same person produces quadrillions of cells.
Over time, an individual cell is damaged again and again. In some cases, they repair themselves thousands of times a day.
“Every once in a while, the cell makes a mistake during DNA repair, or misses one — and that’s a change that gets propagated on,” Conrad said. “Our work gives us a window to the extent that those changes occur in different organs and tissues, and during different periods of our lives.”
This situation, known as somatic mosaicism, is a result of cells mutating from the original DNA blueprint.
Postzygotic DNA mutations accumulate in the human body,
are copied into RNA, and are detected by RNA-seq
A developmental map of these mutations resolves when and where in the body they occur and finds that the selection pressure on PZMs is different from inherited germline variants. BAMs, binary alignment maps; VCF, variant call format.
Building the atlas
Until now, genetic research investigating mutations that occur after fertilization has generally been conducted in biopsies of cancerous tissue, such as skin melanomas and lung tumors, or in easily accessible tissues such as blood.
The new atlas opens a field of inquiry into mutations that occur over the course of a lifetime.
“Going from a single cell to a child is a remarkable process,” said lead author Nicole Rockweiler, Ph.D., previously part of Conrad’s lab at OHSU and Washington University in St. Louis, and now a postdoctoral associate at the Broad Institute of Massachusetts Institute of Technology and Harvard University. “When you add on layers of mutations happening at such an important part of our lives, it’s amazing that we can come out pretty well at the end of our gestation.”
To generate the new atlas, researchers developed a computational method using bulk RNA sequencing to characterize the mutations in a massive catalogue of tissue samples throughout the body. They were able to trace the point at which mutations occurred by mapping them to a “developmental tree,” indexing them across tissues and among many people. They found many mutations arose systematically and somewhat predictably as people age, although roughly 10% of mutations appeared to be the result of something intrinsic to an individual, be it genes or environment.
They found most detectable mutations occurred later in life, although many occurred before birth.
“We learned that some tissues, like the esophagus and liver, acquire a lot of mutations, whereas other tissues like the brain acquire fewer mutations,” Rockweiler writes in a post on the Conrad Lab website describing the research. “This made sense to us because the esophagus and liver are exposed to many environmental toxins; here the cells must transmit the message in a noisy environment. A low number of mutations in the brain also makes sense because the brain is primarily composed of cells that don’t replicate.”
Source – Oregon Health & Science University
"Kwa mamia ya wafadhili wa tishu, ni mwongozo mkubwa zaidi uliowahi kuundwa; inaweza kusababisha utambuzi bora, matibabu ya magonjwa yanayohusiana na ""bahati mbaya au tabia mbaya"" Watafiti wameunda atlas kubwa zaidi ya mabadiliko ya genome baada ya uzazi katika tishu ya binadamu yenye afya iliyowahi kukusanywa - maendeleo ya kisayansi ambayo yanaweza kufungua njia mpya za kugundua na kutibu magonjwa ya urithi." Ni kubwa zaidi kuwahi kutokea kwa suala la idadi ya pamoja ya tishu na idadi ya wafadhili waliochukuliwa sampuli. Utafiti huo unaonyesha njia ya kuelewa misingi ya maumbile ya magonjwa yanayohusiana na kansa, pamoja na hali nyingi zinazosababishwa na kasoro za seli, ikiwa ni pamoja na kuzeeka. Atlas hiyo inaweza kuwa na manufaa katika kugundua magonjwa na huenda ikawa na manufaa katika kurekebisha mabadiliko ya chembe za urithi yanayosababisha magonjwa. "Ikiwa unazungumza juu ya mabadiliko ya maumbile kuwa msingi wa ugonjwa, kuna teknolojia mbalimbali sasa ambazo zinaturuhusu kufanya mabadiliko kwenye genome, ""alisema mwandishi mwandamizi Don Conrad, Ph.D., profesa msaidizi na mkuu wa Idara ya Genetics katika OHSU's Oregon National Primate Research Center." "Hii ni kwa sababu ya mabadiliko ya chembe za urithi, ambayo inaweza kuwa ""simu ya chembe"" au ""simu ya chembe"" - kwa mfano, chembe za urithi zilizopatikana baada ya kifo cha watu 948 waliotoa miili yao kwa ajili ya Programu ya Ufafanuzi wa Genotype-Tissue ya Taasisi ya Kitaifa ya Afya." Kila mtu huanza kama chembe moja wakati wa mimba, akibeba muundo wa DNA ndani ya kiini cha chembe hiyo ya kwanza iliyozaliwa. Kwa kutumia maagizo hayo ya awali ya DNA, chembe hiyo hugawanyika na kugawanyika katika vikundi vikubwa vya chembe ambazo hufanyiza tishu tofauti-tofauti zinazofanya kazi za kipekee mwilini. Kwa kawaida, mtu ana chembe milioni 30 hivi, na katika maisha yake yote, mtu huyo hutoa chembe milioni milioni 4. Baada ya muda, chembe moja huathiriwa tena na tena. Katika visa fulani, wao hujirekebisha maelfu ya mara kwa siku. "Kila mara kwa muda, seli hufanya kosa wakati wa ukarabati wa DNA, au hukosa moja - na hiyo ni mabadiliko ambayo yanaenezwa", Conrad alisema. "Utafiti wetu unatuonyesha jinsi mabadiliko hayo yanavyotokea katika viungo na tishu tofauti, na katika vipindi tofauti vya maisha yetu. Hali hii, inayojulikana kama somatic mosaicism, ni matokeo ya chembe kubadilika kutoka kwa muundo wa awali wa DNA. """ Mabadiliko ya DNA ya postzygotic hukusanyika katika mwili wa binadamu, na kuunganishwa katika RNA, na kugundua kwa RNA-seq. ramani ya maendeleo ya mabadiliko haya huamua wakati na wapi katika mwili hutokea na hupata kwamba shinikizo la uteuzi juu ya PZM ni tofauti na chembe za urithi. BAMs (Binary Alignment Maps) ni aina ya ramani ya binary. Utafiti wa chembe za urithi unaochunguza mabadiliko ya chembe za urithi baada ya uzazi umefanywa kwa kawaida katika viini vya tishu za kansa, kama vile melanomas za ngozi na uvimbe wa mapafu, au katika tishu zinazopatikana kwa urahisi kama vile damu. Atlas hiyo mpya inafungua njia mpya ya kuchunguza mabadiliko yanayotokea katika maisha ya mtu. "Kutoka kwa seli moja hadi mtoto ni mchakato wa ajabu, ""alisema mwandishi mkuu Nicole Rockweiler, Ph.D., ambaye hapo awali alikuwa sehemu ya maabara ya Conrad katika OHSU na Chuo Kikuu cha Washington huko St. Louis, na sasa ni msaidizi wa postdoctoral katika Taasisi ya Broad ya Taasisi ya Teknolojia ya Massachusetts na Chuo Kikuu cha Harvard." "Wakati unapoongeza juu ya tabaka za mabadiliko yanayotokea katika sehemu muhimu kama hiyo ya maisha yetu, ni ya kushangaza kwamba tunaweza kutoka vizuri sana mwishoni mwa ujauzito wetu. ""Kutengeneza atlas mpya, watafiti waliendeleza njia ya hesabu kwa kutumia mpangilio wa RNA kwa wingi ili kuelezea mabadiliko katika orodha kubwa ya sampuli za tishu katika mwili wote." Waliweza kufuatilia hatua ambayo mabadiliko yalitokea kwa kuyaweka kwenye "mti wa maendeleo", kuorodhesha kwenye tishu na kati ya watu wengi. Watafiti walipata kwamba mabadiliko mengi ya chembe za urithi hutokea kwa utaratibu na kwa njia inayoweza kutabiriwa kadiri watu wanavyozeeka, ingawa asilimia 10 ya mabadiliko ya chembe za urithi huonekana kuwa matokeo ya kitu cha ndani cha mtu, iwe ni chembe za urithi au mazingira. Walipata kwamba mabadiliko mengi yanayoweza kugunduliwa yalitokea baadaye maishani, ingawa mengi yalitokea kabla ya kuzaliwa. "Tumejifunza kwamba baadhi ya tishu, kama vile esophagus na ini, hupata mabadiliko mengi, wakati tishu nyingine kama vile ubongo hupata mabadiliko machache, ""Rockweiler anaandika katika chapisho kwenye tovuti ya Conrad Lab kuelezea utafiti. """ <unk>Hii ilikuwa na maana kwetu kwa sababu esophagus na ini ni wazi kwa sumu nyingi za mazingira; hapa seli lazima kusambaza ujumbe katika mazingira ya kelele. Idadi ndogo ya mabadiliko katika ubongo pia ina maana kwa sababu ubongo ni hasa inajumuisha seli ambayo si <unk> kuiga. <unk> Chanzo <unk> Oregon Afya & Sayansi Chuo Kikuu