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Inferring Transmission Histories of Rare Alleles in Population-Scale Genealogies
- Source :
- The American Journal of Human Genetics. 103:893-906
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Learning the transmission history of alleles through a family or population plays an important role in evolutionary, demographic, and medical genetic studies. Most classical models of population genetics have attempted to do so under the assumption that the genealogy of a population is unavailable and that its idiosyncrasies can be described by a small number of parameters describing population size and mate choice dynamics. Large genetic samples have increased sensitivity to such modeling assumptions, and large-scale genealogical datasets become a useful tool to investigate realistic genealogies. However, analyses in such large datasets are often intractable using conventional methods. We present an efficient method to infer transmission paths of rare alleles through population-scale genealogies. Based on backward-time Monte Carlo simulations of genetic inheritance, we use an importance sampling scheme to dramatically speed up convergence. The approach can take advantage of available genotypes of subsets of individuals in the genealogy including haplotype structure as well as information about the mode of inheritance and general prevalence of a mutation or disease in the population. Using a high-quality genealogical dataset of more than three million married individuals in the Quebec founder population, we apply the method to reconstruct the transmission history of chronic atrial and intestinal dysrhythmia (CAID), a rare recessive disease. We identify the most likely early carriers of the mutation and geographically map the expected carrier rate in the present-day French-Canadian population of Quebec.
- Subjects :
- Male
0301 basic medicine
Population
Population genetics
030105 genetics & heredity
Biology
Article
03 medical and health sciences
Rare Diseases
Population Groups
Databases, Genetic
Genetics
Humans
Allele
education
Alleles
Genetics (clinical)
education.field_of_study
Population size
Small number
Haplotype
Quebec
Biological Evolution
Pedigree
Wills
Genetics, Population
030104 developmental biology
Haplotypes
Evolutionary biology
Mutation
Female
Imputation (genetics)
Founder effect
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 103
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....a46c34fd41cd171aae696e74c1991ba6