Identification of Recessive Lethal Alleles in the Diploid Genome of a <named-content content-type="genus-species">Candida albicans</named-content> Laboratory Strain Unveils a Potential Role of Repetitive Sequences in Buffering Their Deleterious Impact

ABSTRACT The heterozygous diploid genome of Candida albicans is highly plastic, with frequent loss of heterozygosity (LOH) events. In the SC5314 laboratory strain, while LOH events are ubiquitous, a chromosome homozygosis bias is observed for certain chromosomes, whereby only one of the two homologs...

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Autores principales:	Timea Marton, Adeline Feri, Pierre-Henri Commere, Corinne Maufrais, Christophe d’Enfert, Melanie Legrand
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Candida albicans homologous recombination loss of heterozygosity major repeat sequences recessive lethal alleles Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a4f19e583b0040988497b79b9662e61f
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spelling	oai:doaj.org-article:a4f19e583b0040988497b79b9662e61f2021-11-15T15:22:04ZIdentification of Recessive Lethal Alleles in the Diploid Genome of a <named-content content-type="genus-species">Candida albicans</named-content> Laboratory Strain Unveils a Potential Role of Repetitive Sequences in Buffering Their Deleterious Impact10.1128/mSphere.00709-182379-5042https://doaj.org/article/a4f19e583b0040988497b79b9662e61f2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00709-18https://doaj.org/toc/2379-5042ABSTRACT The heterozygous diploid genome of Candida albicans is highly plastic, with frequent loss of heterozygosity (LOH) events. In the SC5314 laboratory strain, while LOH events are ubiquitous, a chromosome homozygosis bias is observed for certain chromosomes, whereby only one of the two homologs can occur in the homozygous state. This suggests the occurrence of recessive lethal allele(s) (RLA) preventing large-scale LOH events on these chromosomes from being stably maintained. To verify the presence of an RLA on chromosome 7 (Chr7), we utilized a system that allows (i) DNA double-strand break (DSB) induction on Chr7 by the I-SceI endonuclease and (ii) detection of the resulting long-range homozygosis. I-SceI successfully induced a DNA DSB on both Chr7 homologs, generally repaired by gene conversion. Notably, cells homozygous for the right arm of Chr7B were not recovered, confirming the presence of RLA(s) in this region. Genome data mining for RLA candidates identified a premature nonsense-generating single nucleotide polymorphism (SNP) within the HapB allele of C7_03400c whose Saccharomyces cerevisiae ortholog encodes the essential Mtr4 RNA helicase. Complementation with a wild-type copy of MTR4 rescued cells homozygous for the right arm of Chr7B, demonstrating that the mtr4K880* RLA is responsible for the Chr7 homozygosis bias in strain SC5314. Furthermore, we observed that the major repeat sequences (MRS) on Chr7 acted as hot spots for interhomolog recombination. Such recombination events provide C. albicans with increased opportunities to survive DNA DSBs whose repair can lead to homozygosis of recessive lethal or deleterious alleles. This might explain the maintenance of MRS in this species. IMPORTANCE Candida albicans is a major fungal pathogen, whose mode of reproduction is mainly clonal. Its genome is highly tolerant to rearrangements, in particular loss of heterozygosity events, known to unmask recessive lethal and deleterious alleles in heterozygous diploid organisms such as C. albicans. By combining a site-specific DSB-inducing system and mining genome sequencing data of 182 C. albicans isolates, we were able to ascribe the chromosome 7 homozygosis bias of the C. albicans laboratory strain SC5314 to an heterozygous SNP introducing a premature STOP codon in the MTR4 gene. We have also proposed genome-wide candidates for new recessive lethal alleles. We additionally observed that the major repeat sequences (MRS) on chromosome 7 acted as hot spots for interhomolog recombination. Maintaining MRS in C. albicans could favor haplotype exchange, of vital importance to LOH events, leading to homozygosis of recessive lethal or deleterious alleles that inevitably accumulate upon clonality.Timea MartonAdeline FeriPierre-Henri CommereCorinne MaufraisChristophe d’EnfertMelanie LegrandAmerican Society for MicrobiologyarticleCandida albicanshomologous recombinationloss of heterozygositymajor repeat sequencesrecessive lethal allelesMicrobiologyQR1-502ENmSphere, Vol 4, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans homologous recombination loss of heterozygosity major repeat sequences recessive lethal alleles Microbiology QR1-502
spellingShingle	Candida albicans homologous recombination loss of heterozygosity major repeat sequences recessive lethal alleles Microbiology QR1-502 Timea Marton Adeline Feri Pierre-Henri Commere Corinne Maufrais Christophe d’Enfert Melanie Legrand Identification of Recessive Lethal Alleles in the Diploid Genome of a <named-content content-type="genus-species">Candida albicans</named-content> Laboratory Strain Unveils a Potential Role of Repetitive Sequences in Buffering Their Deleterious Impact
description	ABSTRACT The heterozygous diploid genome of Candida albicans is highly plastic, with frequent loss of heterozygosity (LOH) events. In the SC5314 laboratory strain, while LOH events are ubiquitous, a chromosome homozygosis bias is observed for certain chromosomes, whereby only one of the two homologs can occur in the homozygous state. This suggests the occurrence of recessive lethal allele(s) (RLA) preventing large-scale LOH events on these chromosomes from being stably maintained. To verify the presence of an RLA on chromosome 7 (Chr7), we utilized a system that allows (i) DNA double-strand break (DSB) induction on Chr7 by the I-SceI endonuclease and (ii) detection of the resulting long-range homozygosis. I-SceI successfully induced a DNA DSB on both Chr7 homologs, generally repaired by gene conversion. Notably, cells homozygous for the right arm of Chr7B were not recovered, confirming the presence of RLA(s) in this region. Genome data mining for RLA candidates identified a premature nonsense-generating single nucleotide polymorphism (SNP) within the HapB allele of C7_03400c whose Saccharomyces cerevisiae ortholog encodes the essential Mtr4 RNA helicase. Complementation with a wild-type copy of MTR4 rescued cells homozygous for the right arm of Chr7B, demonstrating that the mtr4K880* RLA is responsible for the Chr7 homozygosis bias in strain SC5314. Furthermore, we observed that the major repeat sequences (MRS) on Chr7 acted as hot spots for interhomolog recombination. Such recombination events provide C. albicans with increased opportunities to survive DNA DSBs whose repair can lead to homozygosis of recessive lethal or deleterious alleles. This might explain the maintenance of MRS in this species. IMPORTANCE Candida albicans is a major fungal pathogen, whose mode of reproduction is mainly clonal. Its genome is highly tolerant to rearrangements, in particular loss of heterozygosity events, known to unmask recessive lethal and deleterious alleles in heterozygous diploid organisms such as C. albicans. By combining a site-specific DSB-inducing system and mining genome sequencing data of 182 C. albicans isolates, we were able to ascribe the chromosome 7 homozygosis bias of the C. albicans laboratory strain SC5314 to an heterozygous SNP introducing a premature STOP codon in the MTR4 gene. We have also proposed genome-wide candidates for new recessive lethal alleles. We additionally observed that the major repeat sequences (MRS) on chromosome 7 acted as hot spots for interhomolog recombination. Maintaining MRS in C. albicans could favor haplotype exchange, of vital importance to LOH events, leading to homozygosis of recessive lethal or deleterious alleles that inevitably accumulate upon clonality.
format	article
author	Timea Marton Adeline Feri Pierre-Henri Commere Corinne Maufrais Christophe d’Enfert Melanie Legrand
author_facet	Timea Marton Adeline Feri Pierre-Henri Commere Corinne Maufrais Christophe d’Enfert Melanie Legrand
author_sort	Timea Marton
title	Identification of Recessive Lethal Alleles in the Diploid Genome of a <named-content content-type="genus-species">Candida albicans</named-content> Laboratory Strain Unveils a Potential Role of Repetitive Sequences in Buffering Their Deleterious Impact
title_short	Identification of Recessive Lethal Alleles in the Diploid Genome of a <named-content content-type="genus-species">Candida albicans</named-content> Laboratory Strain Unveils a Potential Role of Repetitive Sequences in Buffering Their Deleterious Impact
title_full	Identification of Recessive Lethal Alleles in the Diploid Genome of a <named-content content-type="genus-species">Candida albicans</named-content> Laboratory Strain Unveils a Potential Role of Repetitive Sequences in Buffering Their Deleterious Impact
title_fullStr	Identification of Recessive Lethal Alleles in the Diploid Genome of a <named-content content-type="genus-species">Candida albicans</named-content> Laboratory Strain Unveils a Potential Role of Repetitive Sequences in Buffering Their Deleterious Impact
title_full_unstemmed	Identification of Recessive Lethal Alleles in the Diploid Genome of a <named-content content-type="genus-species">Candida albicans</named-content> Laboratory Strain Unveils a Potential Role of Repetitive Sequences in Buffering Their Deleterious Impact
title_sort	identification of recessive lethal alleles in the diploid genome of a <named-content content-type="genus-species">candida albicans</named-content> laboratory strain unveils a potential role of repetitive sequences in buffering their deleterious impact
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/a4f19e583b0040988497b79b9662e61f
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Identification of Recessive Lethal Alleles in the Diploid Genome of a <named-content content-type="genus-species">Candida albicans</named-content> Laboratory Strain Unveils a Potential Role of Repetitive Sequences in Buffering Their Deleterious Impact

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