Biology subjects

Randhawa, R.

Publications and source records attributed to Randhawa, R..

4 recordsLinked to original sources

bioRxiv2022

Characterization of the Y Chromosome in Newfoundland and Labrador: Evidence of a Founder Effect

The population of Newfoundland and Labrador (NL) is largely derived from settlers who migrated primarily from England and Ireland in the 1700-1800s. Previously described as an isolated founder population, based on historical and demographic studies, data on the genetic ancestry of this population remains fragmentary. Here we describe the largest investigation of patrilineal ancestry in NL. To determine the paternal genetic structure of the population, 1,110 Y chromosomes from an NL based cohort were analyzed using 5,761 Y-specific markers. We identified 160 distinct paternal haplotypes, the majority of which (71.4%) belong to the R1b haplogroup. When NL is compared with global reference populations, the haplotype composition and frequencies of the NL paternal lineages primarily resemble the English and Irish ancestral source populations. There is also evidence for genetic contributions from Basque, French, Portuguese, and Spanish fishermen and early settlers that frequented NL. The population structure shows geographical and religious clustering that can be associated with the settlement of ancestral source populations from England and Ireland. For example, the R1b-M222 haplotype, seen in people of Irish descent, is found clustered in the Irish-settled Southeast region of NL. The clustering and expansion of Y haplotypes in conjunction with the geographical and religious clusters illustrate that limited subsequent in-migration, geographic isolation and societal factors have contributed to the genetic substructure of the NL population and its designation as a founder population.

genomics↗

bioRxiv2022

Newfoundland and Labrador: A mosaic founder population of an Irish and British diaspora from 300 years ago.

The founder population of Newfoundland and Labrador (NL) is a unique genetic resource, in part due to geographic and cultural isolation, where historical records describe a migration of European settlers primarily from Ireland and England to NL in the 18th and 19th centuries. Whilst its historical isolation, and increase prevalence of certain monogenic disorders, have been appreciated, the fine-scale genetic structure and ancestry of the population has not been well described. Understanding the genetic background on which functional, disease causing, genetic variation resides on would aid informed genetic mapping efforts in the Province. Here, we leverage dense genome-wide SNP data on 1,807 NL individuals to reveal fine-scale genetic structure in NL that is clustered around coastal communities and correlated with Christian denomination. We show that the majority of NL European ancestry can be traced back to the south-east and south-west of Ireland and England, respectively. We date a substantial population size bottleneck approximately 10-15 generations ago in NL, associated with increased haplotype sharing and autozygosity. Our results elucidate novel insights into the population history of NL and demonstrate evidence of a population conducive to further genetic studies and biomarker discovery. Significance StatementNewfoundland and Labrador (NL) has been identified as a founder population, though evidence of its magnitude and subsequent isolation is unclear. Here, analysis of 1,807 NL individuals demonstrates population structure associated with geographical isolation in coastal communities and religious denomination (Catholic or Protestant Christian). Further, NL European ancestry primarily descends from settlers from south-east Ireland and south-west England. This history is associated with increased sharing of longer haplotypes in NL, and NL-specific drift in some communities more than others, providing strong evidence of a founder event occurring about 10-15 generations ago. This study elucidates the detailed population structure of NL and shows enrichment for otherwise low frequency functional variants due to genetic drift useful for potential future biomarker discovery studies.

genetics↗

bioRxiv2018

Genome-Scale CRISPR Screening Identifies Novel Human Pluripotent Gene Networks

Human pluripotent stem cells (hPSCs) generate a wide variety of disease-relevant cells that can be used to improve the translation of preclinical research. Despite the potential of hPSCs, their use for genetic screening has been limited because of technical challenges. We developed a renewable Cas9/sgRNA-hPSC library where loss-of-function mutations can be induced at will. Our inducible-mutant hPSC library can be used for an unlimited number of genome-wide screens. We screened for novel genes involved in 3 of the fundamental properties of hPSCs: Their ability to self-renew/survive, their capacity to differentiate into somatic cells, and their inability to survive as single-cell clones. We identified a plethora of novel genes with unidentified roles in hPSCs. These results are available as a resource for the community to increase the understanding of both human development and genetics. In the future, our stem cell library approach will be a powerful tool to identify disease-modifying genes.\n\nVISUAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC=\"FIGDIR/small/323436_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (48K):\norg.highwire.dtl.DTLVardef@5101e4org.highwire.dtl.DTLVardef@5321f2org.highwire.dtl.DTLVardef@1d9c94corg.highwire.dtl.DTLVardef@12ebd53_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2017

P53 toxicity is a hurdle to CRISPR/CAS9 screening and engineering in human pluripotent stem cells

CRISPR/Cas9 has revolutionized our ability to engineer genomes and to conduct genome-wide screens in human cells. While some cell types are easily modified with Cas9, human pluripotent stem cells (hPSCs) poorly tolerate Cas9 and are difficult to engineer. Using a stable Cas9 cell line or transient delivery of ribonucleoproteins (RNPs) we achieved an average insertion or deletion efficiency greater than 80%. This high efficiency made it apparent that double strand breaks (DSBs) induced by Cas9 are toxic and kill most treated hPSCs. Cas9 toxicity creates an obstacle to the high-throughput use CRISPR/Cas9 for genome-engineering and screening in hPSCs. We demonstrated the toxic response is tp53-dependent and the toxic effect of tp53 severely reduces the efficiency of precise genome-engineering in hPSCs. Our results highlight that CRISPR-based therapies derived from hPSCs should proceed with caution. Following engineering, it is critical to monitor for tp53 function, especially in hPSCs which spontaneously acquire tp53 mutations.

molecular biology↗