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New gene “encyclopedias” delve deeper into life’s mechanics

Dec. 22, 2010
Courtesy of the National Human Genome Research Institute
and World Science staff

Eight years ago, the mas­sive Hu­man Ge­nome Proj­ect iden­ti­fied most of the roughly 20,000-25,000 genes in hu­man DNA.

Now, a newly pub­lished pair of cat­a­logs seeks to dig deeper in­to the me­chan­ics of life, though us­ing only fruit flies and round­worms as sim­pler, more con­ven­ient mod­els. The list­ings are in­tend­ed to work as “en­cy­clo­pe­dias” that ex­plain how each gene ac­tu­ally works to de­vel­op and main­tain cells and or­gans.

A newly pub­lished pair of cat­a­logs seeks to dig deeper in­to the me­chan­ics of life, though us­ing only fruit flies and round­worms as sim­pler, more con­ven­ient mod­els. The list­ings are in­tend­ed to work as “en­cy­clo­pe­dias” that ex­plain how each gene ac­tu­ally works to de­vel­op and main­tain cells and or­gans. Above, the round­worm C. elegans. (Im­age cour­tesy free.ed.gov)


Re­search­ers say the work should lead to a bet­ter un­der­stand­ing of hu­mans, since the stud­ies of these sim­pler or­gan­isms have re­vealed many over­lap­ping fea­tures with our ge­nome.

“What we learn from these mod­el or­gan­isms will con­trib­ute greatly to our un­der­stand­ing about the ge­no­mic ba­sis of health and dis­ease in hu­mans,” said Er­ic D. Green, who di­rects the U.S. Na­tional Hu­man Ge­nome Re­search In­sti­tute in Be­thes­da, Md. The two cat­a­logues are the fruit of pro­jects the in­sti­tute launched in 2007, called mod­EN­CODE for mod­el or­gan­ism En­cy­clo­pe­dia of DNA El­e­ments.

The chem­i­cal codes of the genes of the fruit fly, Dro­soph­i­la me­l­an­o­gast­er, and the round­worm, Cae­nor­hab­di­tis el­e­gans, were in­i­tially se­quenced, or “writ­ten out” by re­search­ers as part of the Hu­man Ge­nome Proj­ect.

The new re­sults, by con­trast, “al­low sci­en­tists to beg­in read­ing the ge­nome se­quences, mov­ing from a list of let­ters to de­lin­e­at­ing words and punctua­t­ion marks,” said Elise Fein­gold, pro­gram di­rec­tor over­see­ing the pro­jects at the in­sti­tute. The new find­ings are re­ported in the Dec. 24 is­sue of the jour­nal Sci­ence, with com­pan­ion stud­ies pub­lished in the jour­nal Na­ture’s ad­vance on­line edi­tion and in the jour­nals Ge­nome Re­search and Ge­nome Bi­ol­o­gy.

The pro­jects are meant to com­ple­ment work be­ing done by the af­fil­i­at­ed EN­CODE (for EN­Cy­clo­pe­d Of DNA El­e­ments Con­sor­ti­um) Proj­ect, which is build­ing a com­pre­hen­sive cat­a­log of “func­tional ge­no­mic el­e­ments” in the hu­man ge­nome.

The mod­EN­CODE pro­jects apply to the smaller – and there­fore eas­i­er to un­der­stand – ge­nomes of the fruit fly and the round­worm. Un­like the re­search­ers in the hu­man ef­fort, mod­EN­CODE re­search­ers can con­duct ge­net­ic ex­pe­ri­ments on flies or worms to fol­low up on and val­i­date the cur­rent work.

The re­search­ers stud­ied many dif­fer­ent cell types and de­vel­opmental stages to pro­duce the cat­a­logs of genes and oth­er im­por­tant DNA se­quences. The genes stud­ied in­clude ones that — un­like most bet­ter-stud­ied genes — don’t har­bor code for the pro­duc­tion of pro­teins, com­plex mo­le­cules that car­ry out most of the body’s func­tions. These non-pro­tein cod­ing genes may in­stead gov­ern how ac­tive oth­er genes, or sets of genes, are. Oth­er non-pro­tein cod­ing DNA se­quences un­der in­ves­ti­ga­t­ion in­flu­ence the shapes and dy­nam­ics of chro­mo­somes, the great­er struc­tures that pack­age the ge­net­ic code.

“We now know when these genes are used in the life cy­cle and in­creas­ingly what cells the genes are used in,” said Rob­ert H. Wa­ter­ston, sen­ior au­thor of the round­worm pa­per in Sci­ence and chair of the Uni­vers­ity of Wash­ing­ton’s De­part­ment of Ge­nome Sci­ences. “Putting the pieces to­geth­er has be­gun to re­veal how genes may work in con­cert to pro­duce the mar­vel­ous bi­ol­o­gy of the round­worm and fruit fly.”

“I­den­ti­fica­t­ion of thou­sands of new gene tran­scripts has sig­nif­i­cantly in­creased our knowl­edge of the pro­tein rep­er­toire used in fruit flies,” said Su­san Cel­niker, who co-au­thored the fruit fly pa­per and heads the De­part­ment of Ge­nome Dy­nam­ics at Law­rence Berke­ley Na­tional Lab­o­r­a­to­ry in Ca­li­fornia. “Our work pro­vides new re­sources for stu­dy­ing de­vel­opment, sex de­ter­mina­t­ion and ag­ing.”

The re­search­ers al­so ex­am­ined the or­gan­iz­a­tion and struc­ture of chro­ma­tin in the cells through­out the life stages of each or­gan­ism. Chro­ma­tin is the pro­tein superstruc­ture that pack­ages DNA and mod­u­lates which sec­tions of the ge­nome are ac­ces­si­ble to regulato­ry mo­le­cules that con­vert the ge­net­ic code in­to cel­lu­lar ac­tion. Both groups dis­cov­ered spe­cif­ic chro­ma­tin sig­na­tures as­so­ci­at­ed with the regula­t­ion of pro­tein-cod­ing genes. Un­ique chro­ma­tin sig­na­tures were as­so­ci­at­ed with dis­tinct re­gions of the ge­nome that ei­ther turn genes on or off.

“Chro­ma­tin sig­na­tures are emerg­ing as a pow­er­ful lens in­to the struc­ture and func­tion of the regulato­ry por­tion of the ge­nome that con­trols cell ac­ti­vity,” said Mano­lis Kel­lis, sen­ior au­thor of the fruit fly pa­per and a com­put­er sci­ent­ist at the Mas­sa­chu­setts In­sti­tute of Tech­nol­o­gy.


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Eight years ago, the massive Human Genome Project identified most of the roughly 20,000-25,000 genes in human DNA. Now, a newly published pair of catalogs seeks to dig deeper into the mechanics of life, though using only fruit flies and roundworms as simpler, more convenient models. The listings are intended to work as “encyclopedias” that explain how each gene actually works to develop and maintain cells and organs. Researchers say the work should lead to a better understanding of humans, since the studies of these simpler organisms have revealed many overlapping features with our genome. “What we learn from these model organisms will contribute greatly to our understanding about the genomic basis of health and disease in humans,” said Eric D. Green, who directs the U.S. National Human Genome Research Institute in Bethesda, Md. The two catalogues are the fruit of projects the institute launched in 2007, called modENCODE for “model organism Encyclopedia of DNA Elements. The chemical codes of the genes of the fruit fly, Drosophila melanogaster, and the roundworm, Caenorhabditis elegans, were initially sequenced, or “written out” by researchers as part of the Human Genome Project. The new results, by contrast, “allow scientists to begin reading the genome sequences, moving from a list of letters to delineating words and punctuation marks,” said Elise Feingold, program director overseeing the projects at the institute. The new findings are reported in the Dec. 24 issue of the journal Science, with companion studies published in the journal Nature’s advance online edition and in the journals Genome Research and Genome Biology. The projects are meant to complement work being done by the affiliated ENCODE (for ENCyclopedia Of DNA Elements Consortium) Project, which is building a comprehensive catalog of “functional genomic elements” in the human genome. The modENCODE projects apply to the smaller – and therefore easier to understand – genomes of the fruit fly and the roundworm. Unlike the researchers in the human effort, modENCODE researchers can conduct genetic experiments on flies or worms to follow up on and validate the current work. The researchers studied many different cell types and developmental stages to produce the catalogs of genes and other important DNA sequences. The genes studied include ones that — unlike most better-studied genes — don’t harbor code for the production of proteins, complex molecules that carry out most of the body’s functions. These non-protein coding genes may instead govern how active other genes, or sets of genes, are. Other non-protein coding DNA sequences under investigation influence the shapes and dynamics of chromosomes, the greater structures that package the genetic code. “We now know when these genes are used in the life cycle and increasingly what cells the genes are used in,” said Robert H. Waterston, senior author of the roundworm paper in Science and chair of the Department of Genome Sciences, University of Washington in Seattle. “Putting the pieces together has begun to reveal how genes may work in concert to produce the marvelous biology of the roundworm and fruit fly.” “Identification of thousands of new gene transcripts has significantly increased our knowledge of the protein repertoire used in fruit flies,” said Susan Celniker, co-author of the fruit fly paper and head of the Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, Calif. “Our work provides new resources for studying development, sex determination and aging.” The researchers also examined the organization and structure of chromatin in the cells throughout the life stages of each organism. Chromatin is the protein superstructure that packages DNA and modulates which sections of the genome are accessible to regulatory molecules that convert the genetic code into cellular action. Both groups discovered specific chromatin signatures associated with the regulation of protein-coding genes. Unique chromatin signatures were associated with distinct regions of the genome that either turn genes on or off. “Chromatin signatures are emerging as a powerful lens into the structure and function of the regulatory portion of the genome that controls cell activity,” said Manolis Kellis, senior author of the fruit fly paper and a computer scientist at the Massachusetts Institute of Technology, Cambridge.