Marriage between close biological relatives is generally regarded with suspicion and distaste within Western society, reflecting historical and religious prejudice. By comparison, in many other populations there is a strong preference for consanguineous unions, most frequently contracted between first cousins, and marriage outside the family is perceived as a risky and disruptive option. The increasing importance of the genetic contribution to the overall disease profile in both developed and developing countries has highlighted potential problems associated with detrimental recessive gene expression in consanguineous progeny. This review examines the outcomes of consanguineous unions, with proposals as to how the ongoing preference for consanguinity in many communities can best be accommodated from a clinical genetics perspective.

Consanguinity and its relevance to clinical genetics

There is little information on inbreeding during the critical early years of human existence. However, given the small founding group sizes and restricted mate choices it seems inevitable that intrafamilial reproduction occurred and the resultant levels of inbreeding would have been substantial. Currently, couples related as second cousins or closer (F ≥ 0.0156) and their progeny account for an estimated 10.4% of the global population. The highest rates of consanguineous marriage occur in north and sub-Saharan Africa, the Middle East, and west, central, and south Asia. In these regions even couples who regard themselves as unrelated may exhibit high levels of homozygosity, because marriage within clan, tribe, caste, or biraderi boundaries has been a long-established tradition. Mortality in first-cousin progeny is ≈3.5% higher than in nonconsanguineous offspring, although demographic, social, and economic factors can significantly influence the outcome. Improving socioeconomic conditions and better access to health care will impact the effects of consanguinity, with a shift from infant and childhood mortality to extended morbidity. At the same time, a range of primarily social factors, including urbanization, improved female education, and smaller family sizes indicate that the global prevalence of consanguineous unions will decline. This shift in marriage patterns will initially result in decreased homozygosity, accompanied by a reduction in the expression of recessive single-gene disorders. Although the roles of common and rare gene variants in the etiology of complex disease remain contentious, it would be expected that declining consanguinity would also be reflected in reduced prevalence of complex diseases, especially in population isolates.

/pdf/consanguinity-human-evolution-and-complex-diseases-10ptcj7jiy.pdf

Consanguinity, human evolution, and complex diseases

An essential guide to this major contemporary issue, Consanguinity in Context is a uniquely comprehensive account of intra-familial marriage. Detailed information on past and present religious, social, and legal practices and prohibitions is presented as a backdrop to the preferences and beliefs of the 1100+ million people in consanguineous unions. Chapters on population genetics, and the role of consanguinity in reproductive behaviour and genetic variation, set the scene for critical analyses of the influence of consanguinity in the early years of life. The discussion on consanguinity and disorders of adulthood is the first review of its kind and is particularly relevant given the ageing of the global population. Incest is treated as a separate issue, with historical and present-day examples examined. The final three chapters deal in detail with practical issues, including genetic testing, education and counselling, national and international legislation and imperatives, and the future of consanguineous marriage worldwide.

Consanguinity in Context: Contents

Inbreeding depression, the deterioration in mean trait value in progeny of related parents, is a fundamental quantity in genetics, evolutionary biology, animal and plant breeding, and conservation biology. The magnitude of inbreeding depression can be quantified by the inbreeding load, typically measured in numbers of lethal equivalents, a population genetic quantity that allows for comparisons between environments, populations or species. However, there is as yet no quantitative assessment of which combinations of statistical models and metrics of inbreeding can yield such estimates. Here, we review statistical models that have been used to estimate inbreeding load and use population genetic simulations to investigate how unbiased estimates can be obtained using genomic and pedigree-based metrics of inbreeding. We use simulated binary viability data (i.e., dead versus alive) as our example, but the concepts apply to any trait that exhibits inbreeding depression. We show that the increasingly popular generalized linear models with logit link do not provide comparable and unbiased population genetic measures of inbreeding load, independent of the metric of inbreeding used. Runs of homozygosity result in unbiased estimates of inbreeding load, whereas inbreeding measured from pedigrees results in slight overestimates. Due to widespread use of models that do not yield unbiased measures of the inbreeding load, some estimates in the literature cannot be compared meaningfully. We surveyed the literature for reliable estimates of the mean inbreeding load from wild vertebrate populations and found an average of 3.5 haploid lethal equivalents for survival to sexual maturity. To obtain comparable estimates, we encourage researchers to use generalized linear models with logarithmic links or maximum-likelihood estimation of the exponential equation, and inbreeding coefficients calculated from runs of homozygosity, provided an assembled reference genome of sufficient quality and enough genetic marker data are available.

https://www.zora.uzh.ch/id/eprint/161087/1/Nietlisbach_et_al-2018-Evolutionary_Applications.pdf

Nonequivalent lethal equivalents: Models and inbreeding metrics for unbiased estimation of inbreeding load.

The effects of inbreeding on human health depend critically on the number and severity of recessive, deleterious mutations carried by individuals. In humans, existing estimates of these quantities are based on comparisons between consanguineous and nonconsanguineous couples, an approach that confounds socioeconomic and genetic effects of inbreeding. To overcome this limitation, we focused on a founder population that practices a communal lifestyle, for which there is almost complete Mendelian disease ascertainment and a known pedigree. Focusing on recessive lethal diseases and simulating allele transmissions, we estimated that each haploid set of human autosomes carries on average 0.29 (95% credible interval [0.10, 0.84]) recessive alleles that lead to complete sterility or death by reproductive age when homozygous. Comparison to existing estimates in humans suggests that a substantial fraction of the total burden imposed by recessive deleterious variants is due to single mutations that lead to sterility or death between birth and reproductive age. In turn, comparison to estimates from other eukaryotes points to a surprising constancy of the average number of recessive lethal mutations across organisms with markedly different genome sizes.

https://www.genetics.org/content/genetics/199/4/1243.full.pdf

An Estimate of the Average Number of Recessive Lethal Mutations Carried by Humans

One of the earliest specific demonstrations of inbreeding effects in man was reported in 1902 when Garrod showed that of eighteen cases of the inborn error of metabolism alkaptonuria diagnosed in Europe and North America, twelve had been born to parents who were first cousins. However, in order to maintain a sense of perspective on the level of morbidity resulting from consanguinity, Garrod reminded his readership of the extreme rarity of the condition in first cousin offspring as a whole. In London, only six alkaptonuries had been detected among the estimated 50,000 first cousin progeny then resident in the city. Unfortunately this balanced approach to the effects of human inbreeding has not always been followed. As a result, the high rates of specific disorders identified in particular endogamous groups frequently have been inappropriately adopted by other workers as the bases for predictions on the probable effects of inbreeding in large human populations or even in the entire species. It must be stressed that while inbreeding maybe costly in families or groups known to carry recessive lethal or sub-lethal genes, this outcome is by no means inevitable. The aim of the present chapter is therefore to provide an overall assessment of the risks associated with various degrees of human inbreeding at the population, as opposed to the individual or group, level.

Inbreeding in human populations: An assessment of the costs

A range of mathematical models and error distributions was used to examine the validity of linear regression methods for the calculation of lethal gene equivalents. Because of the restricted span of inbreeding coefficient F values available in human studies and the limited number of data points, equivalent results were obtained with all combinations tested. It was concluded that linear regressions should be employed only for the detection of significant inbreeding effects in man and that their application to the estimation of lethal gene equivalents was not warranted.

/pdf/on-the-choice-of-mathematical-models-for-the-estimation-of-t18p86qimv.pdf

On the choice of mathematical models for the estimation of lethal gene equivalents in man

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Inbreeding in human populations: An assessment of the costs

On the choice of mathematical models for the estimation of lethal gene equivalents in man