Sarath Babu Krishna Murthy, Sandy Yang, Shiraz Bheda, Nikita Tomar, Haiyue Li, Amir Yaghoobi, Atlas Khan, Krzysztof Kiryluk, Joshua E. Motelow, Nick Ren, Ali G. Gharavi, Hila Milo Rasouly
{"title":"利用区域等位基因频率协助分析插入和缺失。","authors":"Sarath Babu Krishna Murthy, Sandy Yang, Shiraz Bheda, Nikita Tomar, Haiyue Li, Amir Yaghoobi, Atlas Khan, Krzysztof Kiryluk, Joshua E. Motelow, Nick Ren, Ali G. Gharavi, Hila Milo Rasouly","doi":"10.1007/s10142-024-01358-3","DOIUrl":null,"url":null,"abstract":"<div><p>Accurate estimation of population allele frequency (AF) is crucial for gene discovery and genetic diagnostics. However, determining AF for frameshift-inducing small insertions and deletions (indels) faces challenges due to discrepancies in mapping and variant calling methods. Here, we propose an innovative approach to assess indel AF. We developed CRAFTS-indels (Calculating Regional Allele Frequency Targeting Small indels), an algorithm that combines AF of distinct indels within a given region and provides “regional AF” (rAF). We tested and validated CRAFTS-indels using three independent datasets: gnomAD v2 (<i>n</i>=125,748 samples), an internal dataset (IGM; <i>n</i>=39,367), and the UK BioBank (UKBB; <i>n</i>=469,835). By comparing rAF against standard AF, we identified rare indels with rAF exceeding standard AF (sAF≤10<sup>-4</sup> and rAF>10<sup>-4</sup>) as “rAF-hi” indels. Notably, a high percentage of rare indels were “rAF-hi”, with a higher proportion in gnomAD v2 (11-20%) and IGM (11-22%) compared to the UKBB (5-9% depending on the CRAFTS-indels’ parameters). Analysis of the overlap of regions based on their rAF with low complexity regions and with ClinVar classification supported the pertinence of rAF. Using the internal dataset, we illustrated the utility of CRAFTS-indel in the analysis of de novo variants and the potential negative impact of rAF-hi indels in gene discovery. In summary, annotation of indels with cohort specific rAF can be used to handle some of the limitations of current annotation pipelines and facilitate detection of novel gene disease associations. CRAFTS-indels offers a user-friendly approach to providing rAF annotation. It can be integrated into public databases such as gnomAD, UKBB and used by ClinVar to revise indel classifications.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":null,"pages":null},"PeriodicalIF":3.9000,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Assisting the analysis of insertions and deletions using regional allele frequencies\",\"authors\":\"Sarath Babu Krishna Murthy, Sandy Yang, Shiraz Bheda, Nikita Tomar, Haiyue Li, Amir Yaghoobi, Atlas Khan, Krzysztof Kiryluk, Joshua E. Motelow, Nick Ren, Ali G. Gharavi, Hila Milo Rasouly\",\"doi\":\"10.1007/s10142-024-01358-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Accurate estimation of population allele frequency (AF) is crucial for gene discovery and genetic diagnostics. However, determining AF for frameshift-inducing small insertions and deletions (indels) faces challenges due to discrepancies in mapping and variant calling methods. Here, we propose an innovative approach to assess indel AF. We developed CRAFTS-indels (Calculating Regional Allele Frequency Targeting Small indels), an algorithm that combines AF of distinct indels within a given region and provides “regional AF” (rAF). We tested and validated CRAFTS-indels using three independent datasets: gnomAD v2 (<i>n</i>=125,748 samples), an internal dataset (IGM; <i>n</i>=39,367), and the UK BioBank (UKBB; <i>n</i>=469,835). By comparing rAF against standard AF, we identified rare indels with rAF exceeding standard AF (sAF≤10<sup>-4</sup> and rAF>10<sup>-4</sup>) as “rAF-hi” indels. Notably, a high percentage of rare indels were “rAF-hi”, with a higher proportion in gnomAD v2 (11-20%) and IGM (11-22%) compared to the UKBB (5-9% depending on the CRAFTS-indels’ parameters). Analysis of the overlap of regions based on their rAF with low complexity regions and with ClinVar classification supported the pertinence of rAF. Using the internal dataset, we illustrated the utility of CRAFTS-indel in the analysis of de novo variants and the potential negative impact of rAF-hi indels in gene discovery. In summary, annotation of indels with cohort specific rAF can be used to handle some of the limitations of current annotation pipelines and facilitate detection of novel gene disease associations. CRAFTS-indels offers a user-friendly approach to providing rAF annotation. 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Assisting the analysis of insertions and deletions using regional allele frequencies
Accurate estimation of population allele frequency (AF) is crucial for gene discovery and genetic diagnostics. However, determining AF for frameshift-inducing small insertions and deletions (indels) faces challenges due to discrepancies in mapping and variant calling methods. Here, we propose an innovative approach to assess indel AF. We developed CRAFTS-indels (Calculating Regional Allele Frequency Targeting Small indels), an algorithm that combines AF of distinct indels within a given region and provides “regional AF” (rAF). We tested and validated CRAFTS-indels using three independent datasets: gnomAD v2 (n=125,748 samples), an internal dataset (IGM; n=39,367), and the UK BioBank (UKBB; n=469,835). By comparing rAF against standard AF, we identified rare indels with rAF exceeding standard AF (sAF≤10-4 and rAF>10-4) as “rAF-hi” indels. Notably, a high percentage of rare indels were “rAF-hi”, with a higher proportion in gnomAD v2 (11-20%) and IGM (11-22%) compared to the UKBB (5-9% depending on the CRAFTS-indels’ parameters). Analysis of the overlap of regions based on their rAF with low complexity regions and with ClinVar classification supported the pertinence of rAF. Using the internal dataset, we illustrated the utility of CRAFTS-indel in the analysis of de novo variants and the potential negative impact of rAF-hi indels in gene discovery. In summary, annotation of indels with cohort specific rAF can be used to handle some of the limitations of current annotation pipelines and facilitate detection of novel gene disease associations. CRAFTS-indels offers a user-friendly approach to providing rAF annotation. It can be integrated into public databases such as gnomAD, UKBB and used by ClinVar to revise indel classifications.
期刊介绍:
Functional & Integrative Genomics is devoted to large-scale studies of genomes and their functions, including systems analyses of biological processes. The journal will provide the research community an integrated platform where researchers can share, review and discuss their findings on important biological questions that will ultimately enable us to answer the fundamental question: How do genomes work?