A 12 kb multi-allelic copy number variation encompassing a GC gene enhancer is associated with mastitis resistance in dairy cattle

Clinical mastitis (CM) is an inflammatory disease occurring in the mammary glands of lactating cows. CM is under genetic control, and a prominent CM resistance QTL located on chromosome 6 was reported in various dairy cattle breeds. Nevertheless, the biological mechanism underpinning this QTL has been lacking. Herein, we mapped, fine-mapped, and discovered the putative causal variant underlying this CM resistance QTL in the Dutch dairy cattle population. We identified a ~12 kb multi-allelic copy number variant (CNV), that is in perfect linkage disequilibrium with a lead SNP, as a promising candidate variant. By implementing a fine-mapping and through expression QTL mapping, we showed that the group-specific component gene (GC), a gene encoding a vitamin D binding protein, is an excellent candidate causal gene for the QTL. The multiplicated alleles are associated with increased GC expression and low CM resistance. Ample evidence from functional genomics data supports the presence of an enhancer within this CNV, which would exert cis-regulatory effect on GC. We observed that strong positive selection swept the region near the CNV, and haplotypes associated with the multiplicated allele were strongly selected for. Moreover, the multiplicated allele showed pleiotropic effects for increased milk yield and reduced fertility, hinting that a shared underlying biology for these effects may revolve around the vitamin D pathway. These findings together suggest a putative causal variant of a CM resistance QTL, where a cis-regulatory element located within a CNV can alter gene expression and affect multiple economically important traits.

HiCancer: accurate and complete cancer genome phasing with Hi-C reads

Due to the high complexity of cancer genome, it is too difficult to generate complete cancer genome map which contains the sequence of every DNA molecule until now. Nevertheless, phasing each chromosome in cancer genome into two haplotypes according to germline mutations provides a suboptimal solution to understand cancer genome. However, phasing cancer genome is also a challenging problem, due to the limit in experimental and computational technologies. Hi-C data is widely used in phasing in recent years due to its long-range linkage information and provides an opportunity for solving the problem of phasing cancer genome. The existing Hi-C based phasing methods can not be applied to cancer genome directly, because the somatic mutations in cancer genome such as somatic SNPs, copy number variations and structural variations greatly reduce the correctness and completeness. Here, we propose a new Hi-C based pipeline for phasing cancer genome called HiCancer. HiCancer solves different kinds of somatic mutations and variations, and take advantage of allelic copy number imbalance and linkage disequilibrium to improve the correctness and completeness of phasing. According to our experiments in K562 and KBM-7 cell lines, HiCancer is able to generate very high-quality chromosome-level haplotypes for cancer genome with only Hi-C data.

A 12 kb multi-allelic copy number variation encompassing a GC gene enhancer is associated with mastitis resistance in dairy cattle

Clinical mastitis (CM) is an inflammatory disease occurring in the mammary glands of lactating cows. CM is under genetic control, and a prominent CM resistance QTL located on chromosome 6 was reported in various dairy cattle breeds. Nevertheless, the biological mechanism underpinning this QTL has been lacking. Herein, we mapped, fine-mapped, and discovered the putative causal variant underlying this CM resistance QTL in the Dutch dairy cattle population. We identified a ~12 kb multi-allelic copy number variant (CNV), that is in perfect linkage disequilibrium with a GWAS lead SNP, as a promising candidate variant. By implementing a genome-wide association study (GWAS) and through expression QTL mapping, we showed that the group-specific component gene ( GC ), a gene encoding a vitamin D binding protein, is an excellent candidate causal gene for the QTL. The multiplicated alleles are associated with increased GC expression and low CM resistance. Ample evidence from functional genomics data supports the presence of an enhancer within this CNV, which would exert cis -regulatory effect on GC . We observed that strong positive selection swept the region near the CNV, and haplotypes associated with the multiplicated allele were strongly selected for. Moreover, the multiplicated allele showed pleiotropic effects for increased milk yield and reduced fertility, hinting that a shared underlying biology for these effects may revolve around the vitamin D pathway. These findings together suggest a putative causal variant of a CM resistance QTL, where a cis -regulatory element located within a CNV can alter gene expression and affect multiple economically important traits.

Alleloscope: Integrative single cell analysis of allele-specific copy number alterations and chromatin accessibility in cancer

Cancer progression is driven by both somatic copy number aberrations (CNAs) and chromatin remodeling, yet little is known about the interplay between these two classes of events in shaping the clonal diversity of cancers. We present Alleloscope, a method for allele-specific copy number estimation that can be applied to single cell DNA and ATAC sequencing data, either separately or in combination. This approach allows for integrative multi-omic analysis of allele-specific copy number and chromatin accessibility on the same cell. On scDNA-seq data from gastric, colorectal, and breast cancer samples, with extensive validation using matched linked-read sequencing, Alleloscope finds pervasive occurrence of highly complex, multi-allelic copy number aberrations, where cells that carry varying allelic configurations adding to the same total copy number co-evolve within a tumor. The contributions of such allele-specific events to intratumor heterogeneity have been under-reported and under-studied due to the lack of methods for their detection. On scATAC-seq from two basal cell carcinoma samples and a gastric cancer cell line, Alleloscope detects multi-allelic copy number events and copy neutral loss-of-heterozygosity, enabling the dissection of the contributions of chromosomal instability and chromatin remodeling in tumor evolution.

Alleloscope: Integrative single cell analysis of allele-specific copy number alterations and chromatin accessibility in cancer

Cancer progression is driven by both somatic copy number aberrations (CNAs) and chromatin remodeling, yet little is known about the interplay between these two classes of events in shaping the clonal diversity of cancers. We present Alleloscope, a method for allele-specific copy number estimation that can be applied to single cell DNA and ATAC sequencing data, either separately or in combination. This approach allows for integrative multi-omic analysis of allele-specific copy number and chromatin accessibility on the same cell. On scDNA-seq data from gastric, colorectal, and breast cancer samples, with extensive validation using matched linked-read sequencing, Alleloscope finds pervasive occurrence of highly complex, multi-allelic copy number aberrations, where cells that carry varying allelic configurations adding to the same total copy number co-evolve within a tumor. The contributions of such allele-specific events to intratumor heterogeneity have been under-reported and under-studied due to the lack of methods for their detection. On scATAC-seq from two basal cell carcinoma samples and a gastric cancer cell line, Alleloscope detects multi-allelic copy number events and copy neutral loss-of-heterozygosity, enabling the dissection of the contributions of chromosomal instability and chromatin remodeling in tumor evolution.