Evolutionary constraint facilitates interpretation of genetic variation from resequenced human genomes
Abstract/Contents
- Abstract
- I demonstrate how comparative sequence analysis facilitates genome-wide base-pair level interpretation of individual genetic variation, and address three questions of importance for human personal genomics: First, whether an individual's functional variation comes mostly from noncoding or coding polymorphisms; second, whether population-specific or globally present polymorphisms contribute more to functional variation in any given individual; third what is the functional impact of short insertions and deletions in an individual genome. These questions have not been definitively answered by analyses of existing variation data because of a focus on coding polymorphisms, ascertainment biases in favor of common variation, and a lack of base-pair level resolution for identifying functional variants. The data set used in this study consisted of 575 amplicons resequenced in 432 individuals at genomic sites enriched for evolutionary constraint, and variation from 5 published human genomes. Single-site measures of evolutionary constraint derived from mammalian multiple sequence alignments are strongly predictive of reductions in modern-day genetic diversity across a range of annotation categories and across the allele frequency spectrum. I show that putatively functional variation in an individual genome is dominated by polymorphisms that do not change protein sequence, and which originate from our shared ancestral population and commonly segregate in human populations. Furthermore, I demonstrate that selection against short human indels has been shaped by patterns of evolutionary constraint, belying their potential functional importance. These observations show that common, noncoding alleles contribute substantially to human phenotypes and that constraint-based analyses will be of tremendous value to identify phenotypically-relevant variants in individual genomes.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Copyright date | 2011 |
| Publication date | 2010, c2011; 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Goode, David Lloyd | |
|---|---|---|
| Associated with | Stanford University, Department of Genetics | |
| Primary advisor | Sidow, Arend | |
| Thesis advisor | Sidow, Arend | |
| Thesis advisor | Bustamante, Carlos | |
| Thesis advisor | Petrov, Dmitri Alex, 1969- | |
| Thesis advisor | Tang, Hua | |
| Advisor | Bustamante, Carlos | |
| Advisor | Petrov, Dmitri Alex, 1969- | |
| Advisor | Tang, Hua |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | David Goode. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Ph.D. Stanford University 2011 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by David Lloyd Goode
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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