A molecular evolutionary reference for the human variome

Li Liu, Koichiro Tamura, Maxwell Sanderford, Vanessa E. Gray, Sudhir Kumar

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Widespread sequencing efforts are revealing unprecedented amount of genomic variation in populations. Such information is routinely used to derive consensus reference sequences and to infer positions subject to natural selection. Here, we present a new molecular evolutionary method for estimating neutral evolutionary probabilities (EPs) of each amino acid, or nucleotide state at a genomic position without using intraspecific polymorphism data. Because EPs are derived independently of population-level information, they serve as null expectations that can be used to evaluate selective forces on alleles at both polymorphic and monomorphic positions in populations. We applied this method to coding sequences in the human genome and produced a comprehensive evolutionary variome reference for all human proteins. We found that EPs accurately predict neutral and disease- Associated alleles. Through an analysis of discordance between allelic EPs and their observed population frequencies, we discovered thousands of novel candidate sites for nonneutral evolution in human proteins. Many of these were validated in a joint analysis of disease- Associated variants and population data. The EP method is also directly applicable to the analysis of noncoding sequences and genomic analyses of nonmodel species.

Original languageEnglish (US)
Pages (from-to)245-254
Number of pages10
JournalMolecular Biology and Evolution
Volume33
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

genomics
Population
allele
Alleles
alleles
protein
Joint Diseases
Genetic Selection
Consensus Sequence
Human Genome
natural selection
Sequence Analysis
Proteins
polymorphism
Nucleotides
proteins
genome
amino acid
nucleotides
methodology

Keywords

  • Adaptation
  • Disease
  • Evolution
  • Neutrality
  • Phylomedicine

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics

Cite this

A molecular evolutionary reference for the human variome. / Liu, Li; Tamura, Koichiro; Sanderford, Maxwell; Gray, Vanessa E.; Kumar, Sudhir.

In: Molecular Biology and Evolution, Vol. 33, No. 1, 01.01.2016, p. 245-254.

Research output: Contribution to journalArticle

Liu, L, Tamura, K, Sanderford, M, Gray, VE & Kumar, S 2016, 'A molecular evolutionary reference for the human variome', Molecular Biology and Evolution, vol. 33, no. 1, pp. 245-254. https://doi.org/10.1093/molbev/msv198
Liu, Li ; Tamura, Koichiro ; Sanderford, Maxwell ; Gray, Vanessa E. ; Kumar, Sudhir. / A molecular evolutionary reference for the human variome. In: Molecular Biology and Evolution. 2016 ; Vol. 33, No. 1. pp. 245-254.
@article{0b93ba21ecdb4d1ab1e8fea516bcaa8a,
title = "A molecular evolutionary reference for the human variome",
abstract = "Widespread sequencing efforts are revealing unprecedented amount of genomic variation in populations. Such information is routinely used to derive consensus reference sequences and to infer positions subject to natural selection. Here, we present a new molecular evolutionary method for estimating neutral evolutionary probabilities (EPs) of each amino acid, or nucleotide state at a genomic position without using intraspecific polymorphism data. Because EPs are derived independently of population-level information, they serve as null expectations that can be used to evaluate selective forces on alleles at both polymorphic and monomorphic positions in populations. We applied this method to coding sequences in the human genome and produced a comprehensive evolutionary variome reference for all human proteins. We found that EPs accurately predict neutral and disease- Associated alleles. Through an analysis of discordance between allelic EPs and their observed population frequencies, we discovered thousands of novel candidate sites for nonneutral evolution in human proteins. Many of these were validated in a joint analysis of disease- Associated variants and population data. The EP method is also directly applicable to the analysis of noncoding sequences and genomic analyses of nonmodel species.",
keywords = "Adaptation, Disease, Evolution, Neutrality, Phylomedicine",
author = "Li Liu and Koichiro Tamura and Maxwell Sanderford and Gray, {Vanessa E.} and Sudhir Kumar",
year = "2016",
month = "1",
day = "1",
doi = "10.1093/molbev/msv198",
language = "English (US)",
volume = "33",
pages = "245--254",
journal = "Molecular Biology and Evolution",
issn = "0737-4038",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - A molecular evolutionary reference for the human variome

AU - Liu, Li

AU - Tamura, Koichiro

AU - Sanderford, Maxwell

AU - Gray, Vanessa E.

AU - Kumar, Sudhir

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Widespread sequencing efforts are revealing unprecedented amount of genomic variation in populations. Such information is routinely used to derive consensus reference sequences and to infer positions subject to natural selection. Here, we present a new molecular evolutionary method for estimating neutral evolutionary probabilities (EPs) of each amino acid, or nucleotide state at a genomic position without using intraspecific polymorphism data. Because EPs are derived independently of population-level information, they serve as null expectations that can be used to evaluate selective forces on alleles at both polymorphic and monomorphic positions in populations. We applied this method to coding sequences in the human genome and produced a comprehensive evolutionary variome reference for all human proteins. We found that EPs accurately predict neutral and disease- Associated alleles. Through an analysis of discordance between allelic EPs and their observed population frequencies, we discovered thousands of novel candidate sites for nonneutral evolution in human proteins. Many of these were validated in a joint analysis of disease- Associated variants and population data. The EP method is also directly applicable to the analysis of noncoding sequences and genomic analyses of nonmodel species.

AB - Widespread sequencing efforts are revealing unprecedented amount of genomic variation in populations. Such information is routinely used to derive consensus reference sequences and to infer positions subject to natural selection. Here, we present a new molecular evolutionary method for estimating neutral evolutionary probabilities (EPs) of each amino acid, or nucleotide state at a genomic position without using intraspecific polymorphism data. Because EPs are derived independently of population-level information, they serve as null expectations that can be used to evaluate selective forces on alleles at both polymorphic and monomorphic positions in populations. We applied this method to coding sequences in the human genome and produced a comprehensive evolutionary variome reference for all human proteins. We found that EPs accurately predict neutral and disease- Associated alleles. Through an analysis of discordance between allelic EPs and their observed population frequencies, we discovered thousands of novel candidate sites for nonneutral evolution in human proteins. Many of these were validated in a joint analysis of disease- Associated variants and population data. The EP method is also directly applicable to the analysis of noncoding sequences and genomic analyses of nonmodel species.

KW - Adaptation

KW - Disease

KW - Evolution

KW - Neutrality

KW - Phylomedicine

UR - http://www.scopus.com/inward/record.url?scp=84964789939&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964789939&partnerID=8YFLogxK

U2 - 10.1093/molbev/msv198

DO - 10.1093/molbev/msv198

M3 - Article

VL - 33

SP - 245

EP - 254

JO - Molecular Biology and Evolution

JF - Molecular Biology and Evolution

SN - 0737-4038

IS - 1

ER -