Our Research...

Research in the lab is focused on understanding the genetic etiology of Mendelian and complex traits, how human population history and cultural practices influence patterns of genetic variation, and the ways in which these patterns can be harnessed to advance the discovery of genes that underlie human disease. In our investigations, we employ high-throughput genotyping and next-generation sequencing to interrogate genomes in combination with utilizing and developing novel bioinformatics and statistical genetics tools. We are more broadly interested in understanding how the geographic distribution of human genetic variation relates to the susceptibility of different populations to disease, and ultimately how this variation in disease susceptibility reflects the evolutionary history of human populations. Our efforts will provide a foundation for the development of diagnostic and therapeutic strategies that will help reduce the disease-burden of diverse populations.

Trait Mapping

The identification of novel genes and genetic variants underlying Mendelian and complex phenotypes is a necessary step in furthering our understanding of the pathways involved in their processes and in development. For disease phenotypes, such an understanding is a fundamental step toward the development of diagnostic and therapeutic strategies. Dental and nephrological diseases, as well as infectious diseases, can severely affect the quality of life of patients, both physically and psychologically; however, in many cases, they are not fatal. This lack of mortality provides a multigenerational family structure for genetic studies that is ideally suited to identification of the hereditary factors involved in disease risk and pathogenesis.

Ongoing studies in the lab aim to identify genes and variants that underlie both disease and non-disease phenotypes in humans and other organisms, with an emphasis on dental phenotypes. These studies will be performed using state-of-the-art whole-exome and whole-genome sequencing to identify rare genetic variants with potentially large effects on disease risk and causation. The identification of these genes and variants will form the basis for the development of novel diagnostic and therapeutic strategies that will help to reduce the disease-burden of diverse populations.

Collaborators:

Pragna Patel, Ph.D. (University of Southern California)

Caitlin Pepperell, MD. (University of Wisconsin-Madison)

Polycystic Kidney Disease

Polycystic kidney disease (PKD) is a blanket term used to describe a group of illnesses that are characterized by the appearance of fluid filled cysts mainly in the kidneys. They require frequent medical attention and can lead to kidney failure and death unless renal replacement therapy is initiated. PKD is the most common inherited kidney disease in humans, affecting more than 12.5 million people worldwide and accounting for almost 7% of all pediatric renal transplant patients in Canada. Past research has identified a number of biological factors whose disruption causes PKD. However, these studies also found that the severity and speed of development of PKD in patients with the exact same disruption varied greatly, suggesting that other unknown biological factors help to determine its severity and rate of progression. We have been studying a rat model of PKD to understand its biology and to develop new treatment approaches.

We recently identified a rat in our laboratory that does not suffer from PKD, but when mated with a PKD rat, their offspring develop PKD much more rapidly (3 weeks) than is typical for our rat model (6 months). We believe this is caused by a biological factor that the offspring inherit from this rat which speeds up the development of PKD but does not itself cause PKD. This biological factor that we have named Mcy (modifier of cystic disease) may contribute to the variability in PKD severity and speed of development observed in humans.

The goal of this study is to identify the Mcy biological factor. By identifying the Mcy biological factor, the findings of this study will form the basis of future studies to determine the biological processes in which the Mcy biological factor functions, how its disruption speeds up the development of PKD, and its role in PKD in humans. Together, these studies may aid in the development of better treatments for PKD that can reduce patient suffering and the burden it places on healthcare and transplant systems worldwide.

Collaborators:

Harold Aukema, Ph.D. (University of Manitoba)

Funding:

Children's Hospital Research Institute of Manitoba Operating Grant (2016–2017)

Genomic Homozygosity

Homozygosity is one of the most fundamental concepts in genetics. An individual's level of homozygosity is influenced both by ancient migrations, which have left an increasing pattern of homozygosity with increasing distance from Africa, and by recent inbreeding, which generates homozygosity in small populations and in the offspring of relatives. Disentangling the determinants of homozygosity is important in homozygosity mapping, which seeks to identify the genes that underlie rare recessive genetic diseases. We have recently used genome-wide single-nucleotide polymorphism (SNP) data on 64 worldwide human populations represented in the Human Genome Diversity Project and the International HapMap Project to look at global patterns in genomic homozygosity. We found that Native Americans and Pacific Islanders, which lie farthest from Africa along human migration routes, have numerous short tracts of homozygosity remnant from the out-of-Africa migration, while populations of the Middle East and South Asia instead possess distinctive long tracts of homozygosity owing to high levels of inbreeding. Moreover, we found a correlation between the presence of long regions of homozygosity and the occurrence of genes that underlie autosomal dominant diseases. Our results thus far have shed new light on the influence of population history on homozygosity in the human genome, and provide baseline homozygosity patterns that can assist in homozygosity mapping of disease genes.

Ongoing projects in the lab aim to develop improved methods for the identification of homozygous regions in genome-wide single-nucleotide polymorphism (SNP) genotype data and next-generation sequencing data, and for disentangling genomic patterns of autozygosity (identical by decent) from genomic patterns of homozygosity (identical by state). These novel methods will provide significant advances in the potential for identifying recessive variants responsible for Mendelian and complex diseases in diverse populations.

Collaborators:

Zachary Szpiech, Ph.D. (University of California, San Francisco)

Genetics of Asian Indians

Among the factors shaping present-day patterns of human genetic variation, culturally-driven marital practices provide a key instance of an interaction between social and genetic processes. Nowhere should this be more evident than in India, where centuries-old marriage customs have introduced a complex arrangement of 50,000 to 60,000 essentially endogamous hereditary groups into a contemporary population of at least 1,210 million people. Understanding how this extensive social structuring has influenced patterns of genetic variation is important for studies seeking to identify genes that underlie disease in India, as a failure to account for such structuring has the potential to confound the results of these studies. We have recently used genome-wide microsatellite and insertion/deletion genotype data together with variation in the mitochondrial genome's HVS1 region to investigate patterns of genetic variation in one such group of Gujarati Patels, the Chha Gaam Patels (CGP), who comprise individuals from six villages. We showed the descendants from the six villages to be genetically very similar, and to be genetically distinguishable both from non-Gujaratis and from other Gujaratis. Moreover, analysis of Y-chromosomal and mitochondrial haplotypes provided support for both patrilocal and patrilineal practices within the CGP, and a low-level of female gene flow into the CGP, purportedly through the practice of hypergamy among groups. Our results have shed light on the genetic history of the CGP, and provide further evidence on how caste-based social traditions have introduced fine-scale genetic structure into the Hindu population of India that must be taken into account in disease studies.

Onoging studies in the lab aim to further investigate how culturally-driven marital practices have influenced patterns of genetic variation in India using genome-wide single-nucleotide polymorphism (SNP) and next-generation sequence data on both the CGP and similar groups from across India. These studies will lay the foundation for future studies seeking to identify genes and variants that confer an increased risk for diseases that have a high incidence in Asian Indians, such as cardiovascular disease and diabetes.

Collaborators:

Pragna Patel, Ph.D. (University of Southern California)

Genetics of Central African Pygmies

Understanding human evolutionary history has been a major focus of human population genetics since Charles Darwin first proposed a single African origin for anatomically modern humans in 1871. In this context, the genetics of unique human populations provide invaluable insight into the etiology of human adaptation and phenotypic variability, and contribute more generally to an understanding of the colonization of the major continental regions by anatomically modern humans over the past ~60-125,000 years. The Pygmy populations of Central Africa are among the more charismatic of these populations, having captured the imagination of Europeans and others since the time of Homer due to both their short stature and way of life. While numerous theories based on anthropological and candidate gene studies have been proposed for the multifaceted Pygmy phenotype, no large-scale genetic studies have yet been performed to search for its genetic determinants.

We are part of a collaborative effort investigating the genetic basis of the Pygmy phenotype, with an emphasis on their short stature, in a large sample of Central African Pygmies and their immediate non-Pygmy neighbors using a genome-wide association approach. The findings of this study will form the foundation for further studies on the genetics of African Pygmy populations, as well as investigations in other unique populations that share attributes with African Pygmies, such as the Negritos of New Guinea, to illuminate whether their shared attributes reflect convergent evolution as an adaption to shared environmental challenges.

Collaborators:

Noah Rosenberg, Ph.D. (Stanford University)

Evelyne Heyer, Ph.D. (CNRS-MNHN, Paris)

Paul Verdu, Ph.D. (CNRS-MNHN, Paris)

Alain Froment, M.D., Ph.D. (IRD-MNHN, Paris)

Fernando Ramirez Rozzi, Ph.D. (CNRS, Paris)

Funding:

Natural Sciences and Engineering Research Council of Canada Discovery Grant (2015-2020)

Natural Sciences and Engineering Research Council of Canada PhD Studentship (2016–19)

Genetics of Cape Verde

Cape Verde is an archipelago consisting of nine inhabited islands located off the shores of Senegal. Since the initial settlement of the island of Santiago in 1461, successive migratory waves have brought into contact numerous populations with different cultural and ethnic backgrounds, from European settlers to continental Africans who arrived with the expansion of the African slave trade. This has given rise to new social groups with distinctive socio-cultural features, and by the end of the 16th century a newly formed language was reported: the Creole language, a complex linguistic mixture that emerged from the interaction of various European and African source languages. The subsequent emergence of new Creole language varieties have in turn reshaped the ethnic categorization of the various populations living in Cape Verde. Consequently, contemporary Cape Verdean populations likely represent an amalgamation of multiple source European and African groups, with considerable variation in admixture levels across individuals owing to the diverse origins of their different founder populations.

We are part of a collaborative effort to reconstruct the history of both the Creole language varieties and genetic diversity of Creole speaking populations from the various islands of the Cape Verdean archipelago. Documented linguistic variation in Cape Verde obtained by our collaborator Dr. Marlyse Baptista together with recent developments in the analysis of genetic admixture, makes Cape Verde an ideal test location for a joint study of genetic and linguistic variation in an admixed population.

Collaborators:

Noah Rosenberg, Ph.D. (Stanford University)

Paul Verdu, Ph.D. (CNRS-MNHN, Paris)

Marlyse Baptista, Ph.D. (University of Michigan)

Financial Support

Polycystic Kidney Disease:

Children's Hospital Research Institute of Manitoba Operating Grant (OG2016-08; 2016–2017)

Central African Pygmies:

Natural Sciences and Engineering Research Council of Canada Discovery Grant (RGPIN-2015-04739; 2015–2020)

Natural Sciences and Engineering Research Council of Canada Postgraduate Studentship (Doctoral) (Alexandra Blant; 2016–2019)

Medulloblastoma:

Research Manitoba Tri-Council Bridge Funding (Co-Investigator; Primary Investigator: Hao Ding; 2017–2018)