inbreeding/genetics in CMT Research

August 7, 2003

Abstract from American Journal of Human Genetics. 2003 Jul 29

Estimation of the Inbreeding Coefficient through Use of Genomic Data.

Leutenegger AL, Prum B, Genin E, Verny C, Lemainque A, Clerget-Darpoux

F, EA.

Unite de Recherche en Genetique Epidemiologique et Structure des

Populations Humaines, INSERM U535, Villejuif, France; and Department of

Biostatistics, University of Washington, Seattle, WA, USA.

Many linkage studies are performed in inbred populations, either small

isolated populations or large populations with a long tradition of

marriages between relatives. In such populations, there exist very

complex genealogies with unknown loops. Therefore, the true inbreeding

coefficient of an individual is often unknown. Good estimators of the

inbreeding coefficient (f) are important, since it has been shown that

underestimation of f may lead to false linkage conclusions. When an

individual is genotyped for markers spanning the whole genome, it should

be possible to use this genomic information to estimate that

individual's f. To do so, we propose a maximum-likelihood method that

takes marker dependencies into account through a hidden Markov model.

This methodology also allows us to infer the full probability

dostribution of the identity-by-descent (IBD) status of the two alleles

of an individual at each marker along the genome (posterior IBD

probabilities) and provides a variance for the estimates. We simulate a

full genome scan mimicking the true autosomal genome for (1) a

first-cousin pedigree and (2) a quadruple-second-cousin pedigree. In

both cases, we find that our method accurately estimates f for different

marker maps. We also find that the proportion of genome IBD in an

individual with a given genealogy is very variable. The approach is

illustrated with data from a study of demyelinating autosomal recessive

Charcot-Marie-Tooth disease.

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