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Genetic linkage analysis in the age of whole-genome sequencing

Key Points

  • Genetic linkage analysis can be used as a tool for estimating the genetic distance between two loci.

  • In family data, a small recombination fraction between a hypothesized disease locus and a genetic marker is evidence of short distance between the two loci.

  • Linkage analysis is contrasted with family-based association analysis, in which unaffected family members serve as control individuals (in family-based association tests).

  • Single-nucleotide variants (SNVs) generated by whole-genome sequencing (WGS) can be used in linkage analysis.

  • We describe various linkage algorithms and their properties, as well as their implementations.

  • A detailed enumeration of the pertinent steps in linkage analysis provides a guideline for non-specialists on procedures and pitfalls.

Abstract

For many years, linkage analysis was the primary tool used for the genetic mapping of Mendelian and complex traits with familial aggregation. Linkage analysis was largely supplanted by the wide adoption of genome-wide association studies (GWASs). However, with the recent increased use of whole-genome sequencing (WGS), linkage analysis is again emerging as an important and powerful analysis method for the identification of genes involved in disease aetiology, often in conjunction with WGS filtering approaches. Here, we review the principles of linkage analysis and provide practical guidelines for carrying out linkage studies using WGS data.

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Figure 1: Workflow for the whole-genome sequencing filtering approach in human family data.
Figure 2: Linkage information for a first-cousin mating for an autosomal recessive trait and a phase-known autosomal dominant trait.
Figure 3: LOD score curves for a phase-known autosomal dominant pedigree with ten children in the third generation.

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Acknowledgements

This work was supported by the Natural Science Foundation of China grant 31470070 (to J.O.) and the US National Institutes of Health grants R01 DC003594, R01 DC011651 and U54 HG006493 (to S.M.L.).

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PowerPoint slides

Glossary

Genetic mapping

The ordering of loci on a chromosome and the determination of the distances between two adjacent loci. For short distances, the recombination fraction can serve as a measure of genetic distance, with the unit of measurement being the centimorgan (cM); 1 cM = 1% recombination fraction.

Genetic linkage

A phenomenon whereby two alleles, one each at two different loci, are transmitted together from parents to offspring more often than expected by chance. It leads to a recombination fraction smaller than 0.5.

Phenocopies

Individuals that exhibit the phenotype of a Mendelian trait but that are not carriers of a susceptible genotype. Phenocopies were thought to result from non-genetic factors, but genes at locations other than those under current consideration can also lead to (genetic) phenocopies.

Penetrance

The conditional probability of being affected given one of the genotypes at the disease locus, '+ +', '+ d' or 'dd', where 'd' is the disease allele and '+' the non-disease (wild-type) allele. More generally, penetrance is the conditional probability of a phenotype given a genotype.

Recombination

Two alleles, one from each of two loci, can be inherited from one parent but originate from two different grandparents. If the two marker loci are on the same chromosome, a recombination is the result of an odd number of crossovers between the markers.

Crossing over

A cytogenetic phenomenon that occurs during the formation of human gametes (egg or sperm cells). The salient feature of crossing over is that it occurs semi-randomly along chromosomes, with at least one crossover occurring on each chromosome in meiosis.

Recombination fraction

(θ). The expected proportion of recombinant children divided by the total number of recombinant and non-recombinant children. For two loci in close proximity to each other, θ is small owing to the randomness of crossing over, but it increases to 0.5 for loci that are far apart.

LOD score

Z(x) = log10[L(x)/L(∞)] is the logarithm of the likelihood ratio, with the numerator being calculated under the assumption of linkage and the denominator under no linkage. A LOD score of 3.3 or higher has been shown to correspond to a genome-wide significance level of 0.05.

Mendelian inheritance model

The Mendelian laws of inheritance, when applied to variants, stipulate that an individual carries two copies (alleles) of a given nucleotide and passes one of them at random to each of their offspring. Disease may be the result of a single copy of the allele (dominant inheritance) or of two copies (recessive inheritance) in an individual.

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Ott, J., Wang, J. & Leal, S. Genetic linkage analysis in the age of whole-genome sequencing. Nat Rev Genet 16, 275–284 (2015). https://doi.org/10.1038/nrg3908

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