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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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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 |
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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 |
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