Dataset Information

CLD: Rare-variant linkage disequilibrium between genomic regions identifies novel genomic interactions.

ABSTRACT: Linkage disequilibrium (LD) is a fundamental concept in genetics; critical for studying genetic associations and molecular evolution. However, LD measurements are only reliable for common genetic variants, leaving low-frequency variants unanalyzed. In this work, we introduce cumulative LD (cLD), a stable statistic that captures the rare-variant LD between genetic regions, which reflects more biological interactions between variants, in addition to lack of recombination. We derived the theoretical variance of cLD using delta methods to demonstrate its higher stability than LD for rare variants. This property is also verified by bootstrapped simulations using real data. In application, we find cLD reveals an increased genetic association between genes in 3D chromatin interactions, a phenomenon recently reported negatively by calculating standard LD between common variants. Additionally, we show that cLD is higher between gene pairs reported in interaction databases, identifies unreported protein-protein interactions, and reveals interacting genes distinguishing case/control samples in association studies.

SUBMITTER: Wang D

PROVIDER: S-EPMC10758262 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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cLD: Rare-variant linkage disequilibrium between genomic regions identifies novel genomic interactions.

Wang Dinghao D Perera Deshan D He Jingni J Cao Chen C Kossinna Pathum P Li Qing Q Zhang William W Guo Xingyi X Platt Alexander A Wu Jingjing J Zhang Qingrun Q

PLoS genetics 20231218 12

Linkage disequilibrium (LD) is a fundamental concept in genetics; critical for studying genetic associations and molecular evolution. However, LD measurements are only reliable for common genetic variants, leaving low-frequency variants unanalyzed. In this work, we introduce cumulative LD (cLD), a stable statistic that captures the rare-variant LD between genetic regions, which reflects more biological interactions between variants, in addition to lack of recombination. We derived the theoretica ...[more]

PMID: 38109434

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Project description:The Lundehund is an old dog breed with remarkable anatomical features including polydactyly in all four limbs and extraordinary flexibility of the spine. We genotyped 28 Lundehund using the canine Illumina high density beadchip to estimate the effective population size (Ne) and inbreeding coefficients as well as to identify potential regions of positive selection. The decay of linkage disequilibrium was slow with r2=0.95 in 50 kb distance. The last 7-200 generations ago, Ne was at 10-13. An increase of Ne was noted in the very recent generations with a peak value of 19 for Ne at generation 4. The FROH estimated for 50-, 65- and 358-SNP windows were 0.87, 087 and 0.81, respectively. The most likely estimates for FROH after removing identical-by-state segments due to linkage disequilibria were at 0.80-0.81. The extreme loss of heterozygosity has been accumulated through continued inbreeding over 200 generations within a probably closed population with a small effective population size. The mean inbreeding coefficient based on pedigree data for the last 11 generations (FPed=0.10) was strongly biased downwards due to the unknown coancestry of the founders in this pedigree data. The long-range haplotype test identified regions with genes involved in processes of immunity, olfaction, woundhealing and neuronal development as potential targets of selection. The genes QSOX2, BMPR1B and PRRX2 as well as MYOM1 are candidates for selection on the Lundehund characteristics small body size, increased number of digits per paw and extraordinary mobility, respectively. The objectives of the present study were to genotype 28 Lundehund using the canine Illumina high density beadchip (Illumina, San Diego, CA, USA) to estimate the effective population size (Ne) from data on linkage disequilibria (LD). We identified runs of homozygosity (ROH) as regions with a local loss of genetic variation. Inbreeding coefficients were calculated on the basis of pedigree data (FPed) and genotype information (FROH, FIS) to compare the results of these different methods for this population. We applied the long-range haplotype test to search for potential selective sweeps.

Dataset Information

CLD: Rare-variant linkage disequilibrium between genomic regions identifies novel genomic interactions.

Publications

cLD: Rare-variant linkage disequilibrium between genomic regions identifies novel genomic interactions.

Similar Datasets

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