MySQL my.cnf Optimization
Look at this line
[OK] Key buffer size / total MyISAM indexes: 250.0G/131.6G

The sum of all your MyISAM indexes is 131.6G
You should lower key_buffer_size to 140G. This will give back 110G.
I have a little suggestion for you. You may want to consider using a dedicate keycache for each large table. See my Nov 16, 2012 post Cache all mysql table
Look at this line
[!!] InnoDB data size / buffer pool: 2.2G/2.0G

innodb_buffer_pool_size could be raised to 2560M (That's 2.5G)
Look at these lines
read_buffer_size=2G
sort_buffer_size = 2G

Why is so big? If you change both of these to 32M, you can increase max_connections. In fact, do the following right now:
SET @ThrityTwoMeg = 1024 * 1024 * 32
SET GLOBAL read_buffer_size = @ThrityTwoMeg;
SET GLOBAL sort_buffer_size = @ThrityTwoMeg;
SET GLOBAL join_buffer_size = @ThrityTwoMeg;

Then, go rerun mysqltuner.pl and you will see a dramatic difference from 4.1G per thread
BTW go change join_buffer_size to 32M in my.cnf
Give it a Try !!!
UPDATE 2013-04-11 16:53 EDT
I just thought of another change you can make to increase SELECT speed against MyISAM tables. For every MyISAM you need to read a lot from, do this to the table:
ALTER TABLE mydb.mytable ROW_FORMAT=Fixed;

Believe it or not, this will bloat the table 80-100% in size, but SELECTs will go 20-25% faster. I have written about this many times. Here is just few of my posts:

Mar 25, 2011 : Performance implications of MySQL VARCHAR sizes
May 10, 2011 : What is the performance impact of using CHAR vs VARCHAR on a fixed-size field?
Aug 12, 2011 : Which DBMS is good for super-fast reads and a simple data structure?