The Rise of Ge­nomic Su­per­spread­ers

The com­mon an­ces­tor of pla­cen­tal mam­mals prob­a­bly looked like Eo­maia scan­so­ria, the ear­li­est known pla­cen­tal mam­mal, shown here in an artist's re­con­struc­tion based on a 125-mil­lion-year-old fos­sil skele­ton found in China in 2002. Source

by Steven Quis­tad

One hun­dred mil­lion years ago the earth's cli­mate was much warmer than to­day and vast in­land seas stretched across en­tire con­ti­nents. The land was dom­i­nated by charis­matic megafauna that would one day serve as in­spi­ra­tion for Sir Arthur Co­nan Doyle's novel The Lost World. This pe­riod is com­monly re­ferred to as the age of rep­tiles as our pla­cen­tal an­ces­tors were barely vis­i­ble. Yet it was dur­ing this pe­riod that some­thing sig­nif­i­cant hap­pened to them, some­thing that would be­come a ma­jor part of who we are to­day. One hun­dred mil­lion years agoretro­viruses in­fected our an­ces­tors' germline and hitched a ride through evo­lu­tion into the present day where their DNA still ex­ists in all of our genomes. In fact, such retro­virus in­fec­tions oc­curred ~31 sep­a­rate times in our evo­lu­tion and these en­doge­nous retro­viruses (ERV's) ex­panded and now make up an as­tound­ing 8% of our en­tire genome. This means that we owe ~240,000,000 bp of our DNA to these retro­viruses!

Phy­logeny of mam­mals (57) with ERV megafam­i­lies shown as col­ored cir­cles (area is pro­por­tional to the per­cent­age of the ERV loci in the genome rep­re­sented by that fam­ily). The plac­ing of megafam­i­lies on the tree shows rel­a­tive age but not ori­gin (which may be con­sid­er­ably ear­lier). Scale bar shows ap­prox­i­mate dates in host phy­logeny. As­ter­isked taxa are treated as du­pli­cates and ex­cluded from our analy­sis of all ERV fam­i­lies. Name color shows how many IAP loci were found in each species. Source

Retro­viruses usu­ally in­fect so­matic cells; there­fore, when the in­fected cell stops di­vid­ing all prog­eny will van­ish with the last cell of the clone. How­ever, a retro­virus oc­ca­sion­ally in­fects a cell be­long­ing to the germline. Any off­spring that de­velop from this in­fected germline cell will main­tain the provirus and will pass on to their de­scen­dants. The es­tab­lish­ment of an ERV lin­eage be­gins with an ex­oge­nous "founder provirus." In hu­mans each of the 31 fam­i­lies of ERV's rep­re­sents 31 sep­a­rate in­te­gra­tion events that oc­curred dur­ing our evo­lu­tion. These ERV fam­i­lies are able to ex­pand through re­in­fec­tion, retro­trans­po­si­tion, and piggy-back­ing off co-in­fect­ing viruses; rarely they also dou­ble through du­pli­ca­tion of the chro­mo­so­mal seg­ment where they re­side. The to­tal num­bers of copies or loci can range from just a few to thou­sands in dif­fer­ent fam­i­lies. If the func­tion of a par­tic­u­lar vi­ral pro­tein is sub­ject to lit­tle se­lec­tive pres­sure, ran­dom mod­i­fi­ca­tions will even­tu­ally re­sult in a to­tal loss of ex­pres­sion and repli­ca­tion abil­ity. Most of our ERV's are at least 30 mil­lion years old, so it is not sur­pris­ing that many hu­man ERV's have lost the abil­ity to repli­cate and re­in­fect neigh­bor­ing cells due to the ac­cu­mu­la­tion of sub­sti­tu­tions, dele­tions, and in­ser­tions. Thus our genome has be­come a grave­yard of for­merly ac­tive ERV's.

All retro­viruses en­code en­ve­lope pro­teins (the prod­ucts of the env gene), which are re­quired for in­fec­tiv­ity. Re­cent work by Ma­giorki­nis et al. re­vealed that when ERV's lose their env gene, their pro­lif­er­a­tion within a genome is boosted by a fac­tor of ~30. Us­ing an in sil­ico ap­proach the au­thors re­cov­ered ERV loci from 38 mam­malian genomes. They found that ex­pan­sion of an ERV within a genome is neg­a­tively cor­re­lated with env in­tegrity but not with the in­tegrity of other ERV genes. This sug­gests that loss of env in­tegrity pro­vides the virus with some type of se­lec­tive ad­van­tage. In­ter­est­ingly, the dis­tri­b­u­tion of ERV megafam­i­lies within the 38 genomes closely fol­lowed the 20/80 rule, also known as the Pareto prin­ci­ple. This is an ex­pan­sion of power-law dis­tri­b­u­tions that, when ap­plied to in­fec­tious dis­eases for ex­am­ple, states that a small per­cent­age of in­di­vid­u­als within a pop­u­la­tion are re­spon­si­ble for most of the trans­mis­sion events. In this study, 22% of the megafam­i­lies ac­counted for 80% of all the ERV's. The 20/80 rule has been demon­strated in HIV, SARS, and now ERV pro­lif­er­a­tion.

His­togram show­ing (A) how com­mon are ERV fam­i­lies of dif­fer­ent size (B) How many loci in to­tal are in these fam­i­lies. © env in­tegrity (rel­a­tive to gag) for megafam­i­lies and ran­domly se­lected smaller fam­i­lies.  Source

So why would the loss of the env gene in­crease the pro­lif­er­a­tion of an ERV? Af­ter all it seems coun­ter­in­tu­itive that the loss of a func­tional vi­ral re­cep­tor would in­crease its copy num­ber. From the host's per­spec­tive, ac­tive ERV repli­ca­tion, which is oc­cur­ring most of­ten in so­matic cells, risks in­ser­tional mu­ta­ge­n­e­sis. The trans­mem­brane do­main of the Env pro­tein is also known to have im­muno­sup­pres­sive prop­er­ties; bothof these fac­tors would re­duce host fit­ness. From the viruses per­spec­tive, repli­ca­tion through the for­ma­tion of com­plete viri­ons re­quires evad­ing the host in­nate im­mune sys­tem. There­fore, loss of the env gene would se­lect for ERV's that repli­cate solely at the ge­nomic level avoid­ing the host im­mune de­fenses.

More gen­er­ally the sig­nif­i­cant evo­lu­tion­ary suc­cess of en­doge­nous retro­viruses raises many fu­ture ques­tions. How was evo­lu­tion of the host shaped by ERV's? How do ERV's af­fect host gene ex­pres­sion? Are ERV's ubiq­ui­tous in other or­gan­isms be­yond mam­mals? The high preva­lence of ERV's within our own genome pro­vides yet an­other ex­am­ple that we live in world that has been in­ti­mately shaped by the most abun­dant bi­o­log­i­cal en­ti­ties on the planet, the viruses.

Ref­er­ence

Ma­giorki­nis G, Gif­ford RJ, Kat­zourakis A, De Ranter J, Belshaw R (2012). Env-less en­doge­nous retro­viruses are ge­nomic su­per­spread­ers. Proc Natl Acad Sci USA, 109 (19), 7385–7390. PMID 22529376

Steven is a stu­dent in the Uni­ver­sity of Cal­i­for­nia at San Diego/San Diego State Uni­ver­sity In­te­gra­tive Mi­cro­bi­ol­ogy grad­u­ate course.