From mouse to human: evolutionary genomics analysis of human orthologs of essential genes.
Understanding the core set of genes that are necessary for basic developmental functions is one of the central goals in biology. Studies in model organisms identified a significant fraction of essential genes through the analysis of null-mutations that lead to lethality. Recent large-scale next-gene...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-05-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3649967?pdf=render |
| _version_ | 1819070015929843712 |
|---|---|
| author | Benjamin Georgi Benjamin F Voight Maja Bućan |
| author_facet | Benjamin Georgi Benjamin F Voight Maja Bućan |
| author_sort | Benjamin Georgi |
| collection | DOAJ |
| description | Understanding the core set of genes that are necessary for basic developmental functions is one of the central goals in biology. Studies in model organisms identified a significant fraction of essential genes through the analysis of null-mutations that lead to lethality. Recent large-scale next-generation sequencing efforts have provided unprecedented data on genetic variation in human. However, evolutionary and genomic characteristics of human essential genes have never been directly studied on a genome-wide scale. Here we use detailed phenotypic resources available for the mouse and deep genomics sequencing data from human populations to characterize patterns of genetic variation and mutational burden in a set of 2,472 human orthologs of known essential genes in the mouse. Consistent with the action of strong, purifying selection, these genes exhibit comparatively reduced levels of sequence variation, skew in allele frequency towards more rare, and exhibit increased conservation across the primate and rodent lineages relative to the remainder of genes in the genome. In individual genomes we observed ~12 rare mutations within essential genes predicted to be damaging. Consistent with the hypothesis that mutations in essential genes are risk factors for neurodevelopmental disease, we show that de novo variants in patients with Autism Spectrum Disorder are more likely to occur in this collection of genes. While incomplete, our set of human orthologs shows characteristics fully consistent with essential function in human and thus provides a resource to inform and facilitate interpretation of sequence data in studies of human disease. |
| first_indexed | 2024-12-21T16:59:13Z |
| format | Article |
| id | doaj.art-58419f0b9fc74c90b04503a579f891e1 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-21T16:59:13Z |
| publishDate | 2013-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-58419f0b9fc74c90b04503a579f891e12022-12-21T18:56:40ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-05-0195e100348410.1371/journal.pgen.1003484From mouse to human: evolutionary genomics analysis of human orthologs of essential genes.Benjamin GeorgiBenjamin F VoightMaja BućanUnderstanding the core set of genes that are necessary for basic developmental functions is one of the central goals in biology. Studies in model organisms identified a significant fraction of essential genes through the analysis of null-mutations that lead to lethality. Recent large-scale next-generation sequencing efforts have provided unprecedented data on genetic variation in human. However, evolutionary and genomic characteristics of human essential genes have never been directly studied on a genome-wide scale. Here we use detailed phenotypic resources available for the mouse and deep genomics sequencing data from human populations to characterize patterns of genetic variation and mutational burden in a set of 2,472 human orthologs of known essential genes in the mouse. Consistent with the action of strong, purifying selection, these genes exhibit comparatively reduced levels of sequence variation, skew in allele frequency towards more rare, and exhibit increased conservation across the primate and rodent lineages relative to the remainder of genes in the genome. In individual genomes we observed ~12 rare mutations within essential genes predicted to be damaging. Consistent with the hypothesis that mutations in essential genes are risk factors for neurodevelopmental disease, we show that de novo variants in patients with Autism Spectrum Disorder are more likely to occur in this collection of genes. While incomplete, our set of human orthologs shows characteristics fully consistent with essential function in human and thus provides a resource to inform and facilitate interpretation of sequence data in studies of human disease.http://europepmc.org/articles/PMC3649967?pdf=render |
| spellingShingle | Benjamin Georgi Benjamin F Voight Maja Bućan From mouse to human: evolutionary genomics analysis of human orthologs of essential genes. PLoS Genetics |
| title | From mouse to human: evolutionary genomics analysis of human orthologs of essential genes. |
| title_full | From mouse to human: evolutionary genomics analysis of human orthologs of essential genes. |
| title_fullStr | From mouse to human: evolutionary genomics analysis of human orthologs of essential genes. |
| title_full_unstemmed | From mouse to human: evolutionary genomics analysis of human orthologs of essential genes. |
| title_short | From mouse to human: evolutionary genomics analysis of human orthologs of essential genes. |
| title_sort | from mouse to human evolutionary genomics analysis of human orthologs of essential genes |
| url | http://europepmc.org/articles/PMC3649967?pdf=render |
| work_keys_str_mv | AT benjamingeorgi frommousetohumanevolutionarygenomicsanalysisofhumanorthologsofessentialgenes AT benjaminfvoight frommousetohumanevolutionarygenomicsanalysisofhumanorthologsofessentialgenes AT majabucan frommousetohumanevolutionarygenomicsanalysisofhumanorthologsofessentialgenes |