Cargando…

Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing

A major challenge in current exome sequencing in autosomal recessive (AR) families is the lack of an effective method to prioritize single-nucleotide variants (SNVs). AR families are generally too small for linkage analysis, and length of homozygous regions is unreliable for identification of causat...

Descripción completa

Detalles Bibliográficos
Autores principales: Imai, Atsuko, Nakaya, Akihiro, Fahiminiya, Somayyeh, Tétreault, Martine, Majewski, Jacek, Sakata, Yasushi, Takashima, Seiji, Lathrop, Mark, Ott, Jurg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155624/
https://www.ncbi.nlm.nih.gov/pubmed/26143870
http://dx.doi.org/10.1038/srep12028
_version_ 1782475033174605824
author Imai, Atsuko
Nakaya, Akihiro
Fahiminiya, Somayyeh
Tétreault, Martine
Majewski, Jacek
Sakata, Yasushi
Takashima, Seiji
Lathrop, Mark
Ott, Jurg
author_facet Imai, Atsuko
Nakaya, Akihiro
Fahiminiya, Somayyeh
Tétreault, Martine
Majewski, Jacek
Sakata, Yasushi
Takashima, Seiji
Lathrop, Mark
Ott, Jurg
author_sort Imai, Atsuko
collection PubMed
description A major challenge in current exome sequencing in autosomal recessive (AR) families is the lack of an effective method to prioritize single-nucleotide variants (SNVs). AR families are generally too small for linkage analysis, and length of homozygous regions is unreliable for identification of causative variants. Various common filtering steps usually result in a list of candidate variants that cannot be narrowed down further or ranked. To prioritize shortlisted SNVs we consider each homozygous candidate variant together with a set of SNVs flanking it. We compare the resulting array of genotypes between an affected family member and a number of control individuals and argue that, in a family, differences between family member and controls should be larger for a pathogenic variant and SNVs flanking it than for a random variant. We assess differences between arrays in two individuals by the Hamming distance and develop a suitable test statistic, which is expected to be large for a causative variant and flanking SNVs. We prioritize candidate variants based on this statistic and applied our approach to six patients with known pathogenic variants and found these to be in the top 2 to 10 percentiles of ranks.
format Online
Article
Text
id pubmed-5155624
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-51556242016-12-20 Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing Imai, Atsuko Nakaya, Akihiro Fahiminiya, Somayyeh Tétreault, Martine Majewski, Jacek Sakata, Yasushi Takashima, Seiji Lathrop, Mark Ott, Jurg Sci Rep Article A major challenge in current exome sequencing in autosomal recessive (AR) families is the lack of an effective method to prioritize single-nucleotide variants (SNVs). AR families are generally too small for linkage analysis, and length of homozygous regions is unreliable for identification of causative variants. Various common filtering steps usually result in a list of candidate variants that cannot be narrowed down further or ranked. To prioritize shortlisted SNVs we consider each homozygous candidate variant together with a set of SNVs flanking it. We compare the resulting array of genotypes between an affected family member and a number of control individuals and argue that, in a family, differences between family member and controls should be larger for a pathogenic variant and SNVs flanking it than for a random variant. We assess differences between arrays in two individuals by the Hamming distance and develop a suitable test statistic, which is expected to be large for a causative variant and flanking SNVs. We prioritize candidate variants based on this statistic and applied our approach to six patients with known pathogenic variants and found these to be in the top 2 to 10 percentiles of ranks. Nature Publishing Group 2015-07-06 /pmc/articles/PMC5155624/ /pubmed/26143870 http://dx.doi.org/10.1038/srep12028 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Imai, Atsuko
Nakaya, Akihiro
Fahiminiya, Somayyeh
Tétreault, Martine
Majewski, Jacek
Sakata, Yasushi
Takashima, Seiji
Lathrop, Mark
Ott, Jurg
Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing
title Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing
title_full Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing
title_fullStr Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing
title_full_unstemmed Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing
title_short Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing
title_sort beyond homozygosity mapping: family-control analysis based on hamming distance for prioritizing variants in exome sequencing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155624/
https://www.ncbi.nlm.nih.gov/pubmed/26143870
http://dx.doi.org/10.1038/srep12028
work_keys_str_mv AT imaiatsuko beyondhomozygositymappingfamilycontrolanalysisbasedonhammingdistanceforprioritizingvariantsinexomesequencing
AT nakayaakihiro beyondhomozygositymappingfamilycontrolanalysisbasedonhammingdistanceforprioritizingvariantsinexomesequencing
AT fahiminiyasomayyeh beyondhomozygositymappingfamilycontrolanalysisbasedonhammingdistanceforprioritizingvariantsinexomesequencing
AT tetreaultmartine beyondhomozygositymappingfamilycontrolanalysisbasedonhammingdistanceforprioritizingvariantsinexomesequencing
AT majewskijacek beyondhomozygositymappingfamilycontrolanalysisbasedonhammingdistanceforprioritizingvariantsinexomesequencing
AT sakatayasushi beyondhomozygositymappingfamilycontrolanalysisbasedonhammingdistanceforprioritizingvariantsinexomesequencing
AT takashimaseiji beyondhomozygositymappingfamilycontrolanalysisbasedonhammingdistanceforprioritizingvariantsinexomesequencing
AT lathropmark beyondhomozygositymappingfamilycontrolanalysisbasedonhammingdistanceforprioritizingvariantsinexomesequencing
AT ottjurg beyondhomozygositymappingfamilycontrolanalysisbasedonhammingdistanceforprioritizingvariantsinexomesequencing