A macaque's-eye view of human insertions and deletions: Differences in mechanisms

Erika M. Kvikstad, Svitlana Tyekucheva, Francesca Chiaromonte, Kateryna D. Makova

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Insertions and deletions (indels) cause numerous genetic diseases and lead to pronounced evolutionary differences among genomes. The macaque sequences provide an opportunity to gain insights into the mechanisms generating these mutations on a genome-wide scale by establishing the polarity of indels occurring in the human lineage since its divergence from the chimpanzee. Here we apply novel regression techniques and multiscale analyses to demonstrate an extensive regional indel rate variation stemming from local fluctuations in divergence, GC content, male and female recombination rates, proximity to telomeres, and other genomic factors. We find that both replication and, surprisingly, recombination are significantly associated with the occurrence of small indels. Intriguingly, the relative inputs of replication versus recombination differ between insertions and deletions, thus the two types of mutations are likely guided in part by distinct mechanisms. Namely, insertions are more strongly associated with factors linked to recombination, while deletions are mostly associated with replication-related features. Indel as a term misleadingly groups the two types of mutations together by their effect on a sequence alignment. However, here we establish that the correct identification of a small gap as an insertion or a deletion (by use of an outgroup) is crucial to determining its mechanism of origin. In addition to providing novel insights into insertion and deletion mutagenesis, these results will assist in gap penalty modeling and eventually lead to more reliable genomic alignments.

Original languageEnglish (US)
Pages (from-to)1772-1782
Number of pages11
JournalPLoS computational biology
Volume3
Issue number9
DOIs
StatePublished - Sep 1 2007

Fingerprint

Macaca
Genetic Recombination
Deletion
recombination
Insertion
Genes
eyes
mutation
Mutagenesis
Recombination
Mutation
genomics
genome
Replication
divergence
telomeres
genetic disorders
sequence alignment
Genome
Pan troglodytes

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

Cite this

@article{fe45d70fc4844fd2a258387c38affb8d,
title = "A macaque's-eye view of human insertions and deletions: Differences in mechanisms",
abstract = "Insertions and deletions (indels) cause numerous genetic diseases and lead to pronounced evolutionary differences among genomes. The macaque sequences provide an opportunity to gain insights into the mechanisms generating these mutations on a genome-wide scale by establishing the polarity of indels occurring in the human lineage since its divergence from the chimpanzee. Here we apply novel regression techniques and multiscale analyses to demonstrate an extensive regional indel rate variation stemming from local fluctuations in divergence, GC content, male and female recombination rates, proximity to telomeres, and other genomic factors. We find that both replication and, surprisingly, recombination are significantly associated with the occurrence of small indels. Intriguingly, the relative inputs of replication versus recombination differ between insertions and deletions, thus the two types of mutations are likely guided in part by distinct mechanisms. Namely, insertions are more strongly associated with factors linked to recombination, while deletions are mostly associated with replication-related features. Indel as a term misleadingly groups the two types of mutations together by their effect on a sequence alignment. However, here we establish that the correct identification of a small gap as an insertion or a deletion (by use of an outgroup) is crucial to determining its mechanism of origin. In addition to providing novel insights into insertion and deletion mutagenesis, these results will assist in gap penalty modeling and eventually lead to more reliable genomic alignments.",
author = "Kvikstad, {Erika M.} and Svitlana Tyekucheva and Francesca Chiaromonte and Makova, {Kateryna D.}",
year = "2007",
month = "9",
day = "1",
doi = "10.1371/journal.pcbi.0030176",
language = "English (US)",
volume = "3",
pages = "1772--1782",
journal = "PLoS Computational Biology",
issn = "1553-734X",
publisher = "Public Library of Science",
number = "9",

}

A macaque's-eye view of human insertions and deletions : Differences in mechanisms. / Kvikstad, Erika M.; Tyekucheva, Svitlana; Chiaromonte, Francesca; Makova, Kateryna D.

In: PLoS computational biology, Vol. 3, No. 9, 01.09.2007, p. 1772-1782.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A macaque's-eye view of human insertions and deletions

T2 - Differences in mechanisms

AU - Kvikstad, Erika M.

AU - Tyekucheva, Svitlana

AU - Chiaromonte, Francesca

AU - Makova, Kateryna D.

PY - 2007/9/1

Y1 - 2007/9/1

N2 - Insertions and deletions (indels) cause numerous genetic diseases and lead to pronounced evolutionary differences among genomes. The macaque sequences provide an opportunity to gain insights into the mechanisms generating these mutations on a genome-wide scale by establishing the polarity of indels occurring in the human lineage since its divergence from the chimpanzee. Here we apply novel regression techniques and multiscale analyses to demonstrate an extensive regional indel rate variation stemming from local fluctuations in divergence, GC content, male and female recombination rates, proximity to telomeres, and other genomic factors. We find that both replication and, surprisingly, recombination are significantly associated with the occurrence of small indels. Intriguingly, the relative inputs of replication versus recombination differ between insertions and deletions, thus the two types of mutations are likely guided in part by distinct mechanisms. Namely, insertions are more strongly associated with factors linked to recombination, while deletions are mostly associated with replication-related features. Indel as a term misleadingly groups the two types of mutations together by their effect on a sequence alignment. However, here we establish that the correct identification of a small gap as an insertion or a deletion (by use of an outgroup) is crucial to determining its mechanism of origin. In addition to providing novel insights into insertion and deletion mutagenesis, these results will assist in gap penalty modeling and eventually lead to more reliable genomic alignments.

AB - Insertions and deletions (indels) cause numerous genetic diseases and lead to pronounced evolutionary differences among genomes. The macaque sequences provide an opportunity to gain insights into the mechanisms generating these mutations on a genome-wide scale by establishing the polarity of indels occurring in the human lineage since its divergence from the chimpanzee. Here we apply novel regression techniques and multiscale analyses to demonstrate an extensive regional indel rate variation stemming from local fluctuations in divergence, GC content, male and female recombination rates, proximity to telomeres, and other genomic factors. We find that both replication and, surprisingly, recombination are significantly associated with the occurrence of small indels. Intriguingly, the relative inputs of replication versus recombination differ between insertions and deletions, thus the two types of mutations are likely guided in part by distinct mechanisms. Namely, insertions are more strongly associated with factors linked to recombination, while deletions are mostly associated with replication-related features. Indel as a term misleadingly groups the two types of mutations together by their effect on a sequence alignment. However, here we establish that the correct identification of a small gap as an insertion or a deletion (by use of an outgroup) is crucial to determining its mechanism of origin. In addition to providing novel insights into insertion and deletion mutagenesis, these results will assist in gap penalty modeling and eventually lead to more reliable genomic alignments.

UR - http://www.scopus.com/inward/record.url?scp=34848865680&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34848865680&partnerID=8YFLogxK

U2 - 10.1371/journal.pcbi.0030176

DO - 10.1371/journal.pcbi.0030176

M3 - Article

C2 - 17941704

AN - SCOPUS:34848865680

VL - 3

SP - 1772

EP - 1782

JO - PLoS Computational Biology

JF - PLoS Computational Biology

SN - 1553-734X

IS - 9

ER -