Cargando…

Concerning the eXclusion in human genomics: the choice of sex chromosome representation in the human genome drastically affects the number of identified variants

Over the past 30 years, a community of scientists has pieced together every base pair of the human reference genome from telomere to telomere. Interestingly, most human genomics studies omit more than 5% of the genome from their analyses. Under “normal” circumstances, omitting any chromosome(s) from...

Descripción completa

Detalles Bibliográficos
Autores principales: Pinto, Brendan J, O’Connor, Brian, Schatz, Michael C, Zarate, Samantha, Wilson, Melissa A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542555/
https://www.ncbi.nlm.nih.gov/pubmed/37497639
http://dx.doi.org/10.1093/g3journal/jkad169
_version_ 1785114115639869440
author Pinto, Brendan J
O’Connor, Brian
Schatz, Michael C
Zarate, Samantha
Wilson, Melissa A
author_facet Pinto, Brendan J
O’Connor, Brian
Schatz, Michael C
Zarate, Samantha
Wilson, Melissa A
author_sort Pinto, Brendan J
collection PubMed
description Over the past 30 years, a community of scientists has pieced together every base pair of the human reference genome from telomere to telomere. Interestingly, most human genomics studies omit more than 5% of the genome from their analyses. Under “normal” circumstances, omitting any chromosome(s) from an analysis of the human genome would be a cause for concern, with the exception being sex chromosomes. Sex chromosomes in eutherians share an evolutionary origin as an ancestral pair of autosomes. In humans, they share 3 regions of high-sequence identity (∼98–100%), which, along with the unique transmission patterns of the sex chromosomes, introduce technical artifacts in genomic analyses. However, the human X chromosome bears numerous important genes, including more “immune response” genes than any other chromosome, which makes its exclusion irresponsible when sex differences across human diseases are widespread. To better characterize the possible effect of the inclusion/exclusion of the X chromosome on variants called, we conducted a pilot study on the Terra cloud platform to replicate a subset of standard genomic practices using both the CHM13 reference genome and the sex chromosome complement-aware reference genome. We compared the quality of variant calling, expression quantification, and allele-specific expression using these 2 reference genome versions across 50 human samples from the Genotype-Tissue Expression consortium annotated as females. We found that after correction, the whole X chromosome (100%) can generate reliable variant calls, allowing for the inclusion of the whole genome in human genomics analyses as a departure from the status quo of omitting the sex chromosomes from empirical and clinical genomics studies.
format Online
Article
Text
id pubmed-10542555
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-105425552023-10-03 Concerning the eXclusion in human genomics: the choice of sex chromosome representation in the human genome drastically affects the number of identified variants Pinto, Brendan J O’Connor, Brian Schatz, Michael C Zarate, Samantha Wilson, Melissa A G3 (Bethesda) Investigation Over the past 30 years, a community of scientists has pieced together every base pair of the human reference genome from telomere to telomere. Interestingly, most human genomics studies omit more than 5% of the genome from their analyses. Under “normal” circumstances, omitting any chromosome(s) from an analysis of the human genome would be a cause for concern, with the exception being sex chromosomes. Sex chromosomes in eutherians share an evolutionary origin as an ancestral pair of autosomes. In humans, they share 3 regions of high-sequence identity (∼98–100%), which, along with the unique transmission patterns of the sex chromosomes, introduce technical artifacts in genomic analyses. However, the human X chromosome bears numerous important genes, including more “immune response” genes than any other chromosome, which makes its exclusion irresponsible when sex differences across human diseases are widespread. To better characterize the possible effect of the inclusion/exclusion of the X chromosome on variants called, we conducted a pilot study on the Terra cloud platform to replicate a subset of standard genomic practices using both the CHM13 reference genome and the sex chromosome complement-aware reference genome. We compared the quality of variant calling, expression quantification, and allele-specific expression using these 2 reference genome versions across 50 human samples from the Genotype-Tissue Expression consortium annotated as females. We found that after correction, the whole X chromosome (100%) can generate reliable variant calls, allowing for the inclusion of the whole genome in human genomics analyses as a departure from the status quo of omitting the sex chromosomes from empirical and clinical genomics studies. Oxford University Press 2023-07-27 /pmc/articles/PMC10542555/ /pubmed/37497639 http://dx.doi.org/10.1093/g3journal/jkad169 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Investigation
Pinto, Brendan J
O’Connor, Brian
Schatz, Michael C
Zarate, Samantha
Wilson, Melissa A
Concerning the eXclusion in human genomics: the choice of sex chromosome representation in the human genome drastically affects the number of identified variants
title Concerning the eXclusion in human genomics: the choice of sex chromosome representation in the human genome drastically affects the number of identified variants
title_full Concerning the eXclusion in human genomics: the choice of sex chromosome representation in the human genome drastically affects the number of identified variants
title_fullStr Concerning the eXclusion in human genomics: the choice of sex chromosome representation in the human genome drastically affects the number of identified variants
title_full_unstemmed Concerning the eXclusion in human genomics: the choice of sex chromosome representation in the human genome drastically affects the number of identified variants
title_short Concerning the eXclusion in human genomics: the choice of sex chromosome representation in the human genome drastically affects the number of identified variants
title_sort concerning the exclusion in human genomics: the choice of sex chromosome representation in the human genome drastically affects the number of identified variants
topic Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542555/
https://www.ncbi.nlm.nih.gov/pubmed/37497639
http://dx.doi.org/10.1093/g3journal/jkad169
work_keys_str_mv AT pintobrendanj concerningtheexclusioninhumangenomicsthechoiceofsexchromosomerepresentationinthehumangenomedrasticallyaffectsthenumberofidentifiedvariants
AT oconnorbrian concerningtheexclusioninhumangenomicsthechoiceofsexchromosomerepresentationinthehumangenomedrasticallyaffectsthenumberofidentifiedvariants
AT schatzmichaelc concerningtheexclusioninhumangenomicsthechoiceofsexchromosomerepresentationinthehumangenomedrasticallyaffectsthenumberofidentifiedvariants
AT zaratesamantha concerningtheexclusioninhumangenomicsthechoiceofsexchromosomerepresentationinthehumangenomedrasticallyaffectsthenumberofidentifiedvariants
AT wilsonmelissaa concerningtheexclusioninhumangenomicsthechoiceofsexchromosomerepresentationinthehumangenomedrasticallyaffectsthenumberofidentifiedvariants