Multilocus homozygosity mapping and autozygosity patterns

Journal Article · Thu Sep 01 04:00:00 EDT 1994 · American Journal of Human Genetics

OSTI ID:133949

Thompson, E A; Wijsman, E M ^[1]

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1. Univ. of Washington, Seattle, WA (United States)

Exact computation of likelihoods is often not possible for multipoint linkage analyses on complex pedigrees with missing data, such as arise in homozygosity mapping of rare recessive diseases. Markov chain Monte Carlo (MCMC) can provide an estimate of the likelihood function and lod score. Usually, the genotypes of individuals are taken as the latent variables to be sampled in MCMC analyses of computationally intractable genetic problems, but in the case of a very few sampled individuals in an extended pedigree the space of latent variables can be reduced. Our latent variables are the indicators of grandparental origins of genes for each locus and each segregation. This greatly improves the efficiency of MCMC estimates of multilocus lod scores. For homozygosity mapping, in addition to providing estimates of lod scores, MCMC provides posterior probabilities of multilocus patterns of gene identity by descent. Although in the region of the disease locus, the posterior probability of autozygosity may be high for each pedigree, the probability is low that all of a large set of inbred affected individuals exhibit autozygosity. For each segregation, in the absence of interference, the process of grandparental origin is Markov along the chromosome, but the autozygosity of a descendant individual results from grouping segregation patterns. Hence, the multilocus autozygosity of inbred individuals exhibits interesting patterns, with a clumping of autozygous loci, interspersed by small regions of non-autozygosity, these clumps being more widely separated than predicted by a simple Markov process along the chromosome. These patterns also can be analyzed by Monte Carlo, and also have practical implications in homozygosity mapping, where sometimes a heretozygous marker intervenes in a region of homozygosity. These ideas are illustrated by application to some Werner`s Syndrome pedigrees, a very rare recessive disease of premature aging.

• OSTI ID: 133949
• Report Number(s): CONF-941009--; CNN: Grant GM-46255
• Journal Information: American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
99 GENERAL AND MISCELLANEOUS
AGING
EFFICIENCY
GENES
GENETIC MAPPING
GENETICS
GENOTYPE
HEREDITARY DISEASES
HUMAN CHROMOSOMES
MONTE CARLO METHOD
PATIENTS
RECESSIVE MUTATIONS
STATISTICAL MODELS