Genetic Variation in Populations

Robert L. Nussbaum MD, FACP, FACMG , in Thompson & Thompson Genetics in Medicine , 2016

Consanguinity and Inbreeding

Consanguinity, like stratification and positive assortative mating, brings about an increase in the frequency of autosomal recessive disease by increasing the frequency with which carriers of an autosomal recessive disorder mate. Unlike the disorders in stratified populations, in which each subgroup is likely to have a high frequency of a few alleles, the kinds of recessive disorders seen in the offspring of related parents may be very rare and unusual in the population as a whole because consanguineous mating allows an uncommon allele inherited from a heterozygous common ancestor to become homozygous. A similar phenomenon is seen ingenetic isolates, small populations derived from a limited number of common ancestors who tended to mate only among themselves. Mating between two apparently "unrelated" individuals in a genetic isolate may have the same risk for certain recessive conditions as that observed in consanguineous marriages because the individuals are both carriers by inheritance from common ancestors of the isolate, a phenomenon known as inbreeding .

For example, among Ashkenazi Jews in North America, mutant alleles forTay-Sachs disease (GM2 gangliosidosis) ( Case 43 ), discussed in detail inChapter 12, are relatively more common than in other ethnic groups. The frequency of Tay-Sachs disease is 100 times higher in Ashkenazi Jews (1 per 3600) than in most other populations (1 per 360,000). Thus the Tay-Sachs carrier frequency among Ashkenazi Jews is approximately 1 in 30 (q 2 = 1/3600,q = 1/60, 2pq = ≈1/30) as compared to a carrier frequency of approximately 1 in 300 in non-Ashkenazi individuals.

The Evolution of Inbred Social Systems in Spiders and Other Organisms

Leticia Avilés , Jessica Purcell , in Advances in the Study of Behavior, 2012

F Spider Mites

Inbreeding has also arisen multiple times in the Acari ( Norton et al., 1993), but for the most part not in association with group living, except in spider mites (Prostigmata, Tetranychidae) and perhaps some taxa in the Mesostigmata (Mori et al., 1999; Saito, 1997, 2010). Some spider mite species, such as species in the Tetranychid genus Stigmaeopsis in Japan (Saito, 2010), live in extended family groups (two or three overlapping generations) housed by cooperatively built webs that are thought to have an antipredator function (Mori and Saito, 2005). Inbreeding seems to be common in these species, which, much like the social spiders, also exhibit highly female-biased sex ratios (Norton et al., 1993). Individuals in these species may remain in their natal nest throughout their life, or females may disperse to establish new nests. Male dispersal is thought to be rare and females likely disperse fairly short distances (Saito and Mori, 2005). Mitchell (1973) estimated that dispersal may be quite costly and showed that Tetranychus urticae females in uncrowded conditions will often forego dispersal. Females that do disperse will usually mate with a nest mate prior to leaving the natal nest (Mitchell 1973). Inbreeding depression, on the other hand, has been measured in the subsocial spider mite Stigmaeopsis miscanthi, which exhibits intermediate levels of inbreeding in nature. Saito et al. (2000) found no effect of inbreeding on the early survival of brood even after four generations of inbreeding, but they found that female fecundity decreased by at least 50% with increasing levels of inbreeding. They suggest that inbreeding depression due to recessive deleterious alleles may still be present even in species, such as are mites, with male haploidy. At the moment, there is no enough information to speculate on the balance between costs of inbreeding and of inbreeding avoidance or on the factors responsible for the inbred nature of these spider mite systems.

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Risk Assessment and Genetic Counseling

Robert L. Nussbaum MD, FACP, FACMG , in Thompson & Thompson Genetics in Medicine , 2016

Genetic Counseling for Consanguinity

Consanguineous couples sometimes request genetic counseling before they have children because an increased risk for birth defects in their offspring is widely appreciated. In the absence of a family history for a known autosomal recessive condition, we use empirical risk figures for the offspring of consanguineous couples, based on population surveys of birth defects in children born to first-cousin couples compared with nonconsanguineous couples (Table 16-3).

These results provide empirical risk figures in the counseling of first cousins. Although the relative risk for abnormal offspring is higher for related than for unrelated parents, it is still quite low: approximately double in the offspring of first cousins, compared with baseline risk figures for any abnormality of 15 to 20 per 1000 for any child, regardless of consanguinity. This increased risk is not exclusively for single-gene autosomal recessive diseases but includes the entire spectrum of single-gene and complex trait disorders. However, any couple, consanguineous or not, who has a child with a birth defect is at greater risk for having another child with a birth defect in a subsequent pregnancy.

These risk estimates for consanguinity may be slightly inflated given they are derived from communities in which first-cousin marriages are widespread and encouraged. These are societies in which the degree of relationship (coefficient of inbreeding) between two first cousins may actually be greater than the theoretical

due to multiple other lines of relatedness (seeChapter 9). Furthermore, these same societies may also limit marriages to individuals from the same clan, leading to substantial population stratification, which also increases the rate of autosomal recessive disease beyond what might be expected based on mutant allele frequency alone (seeChapter 9).

Inbreeding and Outbreeding☆

K. Ralls , ... J.D. Ballou , in Reference Module in Life Sciences, 2014

Inbreeding Depression in Small Populations

Inbreeding is unavoidable in small, closed populations because all individuals eventually become related to each other. Inbreeding in an effective population of size ( N e) increases at a rate of 1/(2N e), per generation with random mating. For example, in an effective population of size 10, there is a 5% increase in inbreeding per generation. Consequently, small, isolated populations that have existed for many generations are expected to show inbreeding depression. Small populations of plants, fruit flies, a rock wallaby, Florida panthers, greater prairie chickens, and a snake have been found to suffer from inbreeding depression (Frankham, 2005). However, inbreeding depression may not cause declines in population size due to density dependence. Reduced fecundity and survival will only cause a population to decline to extinction if the reproductive rate drops below the replacement level (Frankham et al., 2010).

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Effects of Population Structure in Genome-wide Association Studies

Yurii S. Aulchenko , in Analysis of Complex Disease Association Studies, 2011

Inbreeding

Inbreeding is preferential breeding between (close) relatives. An extreme example of inbreeding is a selfing, a breeding system observed in some plants. Less extreme inbreeding is not uncommon in animal and human populations. Here, the main reasons for inbreeding are usually geographical (e.g., mice live in very small interbred colonies – dems – which are usually established by a few mice and are quite separated from other dems) or cultural (e.g. royal families of Europe).

Clearly, such preferential breeding between relatives violates the assumption of random aggregation, underlying the Hardy-Weinberg principle. Relatives are likely to share the same alleles, inherited from common ancestors. Therefore their progeny has an increased chance of being autozygous – that is, to inherit a copy of exactly the same ancestral allele from both parents. An autozygous genotype is always homozygous, therefore inbreeding should increase the frequency of homozygous, and decrease the frequency of heterozygous, genotypes.

Inbreeding is quantified by the coefficient of inbreeding, which is defined as the probability of autozygosity. This coefficient may characterize an individual, or a population in general, in which case it is defined as the expectation that a random individual from the population is autozygous at a random locus. The coefficient of inbreeding is closely related to the coefficient of kinship, defined earlier for a pair of individuals as the probability that two alleles sampled at random from these individuals are IBD. It is easy to see that the coefficient of inbreeding for a person is the same as the kinship between its parents.

Let us compute the inbreeding coefficient for the person J depicted in Figure 9.2. J is a child of G and H, who are cousins. J could be autozygous at, for example, the "red" allele of founder grand-grand-parent A, which could have been transmitted through the meioses A ⇒ D, D ⇒ G, and G ⇒ J, and also through the path A ⇒ E, E ⇒ H, and H ⇒ J (Fig. 9.2B). What is the chance for J being autozygous for the "red" allele? The probability that this particular founder allele is transmitted to D is 1/2, the same as the probability that the allele is transmitted from D to G, and the probability that the allele is transmitted from G to J. Thus the probability that the "red" allele is transmitted from A to J is 1/2 · 1/2 · 1/2 = 1/23 = 1/8. Likewise is the chance that that allele is transmitted from A to E to H to J, therefore the probability that J would be autozygous for the red allele is 1/23 · 1/23 = 1/26 = 1/64. However, we are interested in autozygosity for any founder allele; and there are four such alleles ("red", "green", "yellow" and "blue", Fig. 9.2B). For any of these the probability of autozygosity is the same, thus the total probability of autozygosity for J is 4 · 1/64 = 1/24 = 1/16.

FIGURE 9.2. Inbred family structure (A) and probability of individual "G" being autozygous for the "Red" ancestral allele. Please refer to color plate section

Now we shall estimate the expected genotypic probability distribution for a person characterized with some arbitrary coefficient of inbreeding, F – or for a population in which average inbreeding is F. Consider a locus with two alleles, A and B, with frequency of B denoted as q, and frequency of A as p = 1 − q. If the person is autozygous for some founder allele, the founder allele may be either A, leading to autozygous genotype AA, or the founder allele may be B, leading to genotype BB. The chance that the founder allele is A is p, and the chance that the founder allele is B is q. If the person is not autozygous, then the expected genotypic frequencies follow HWE. Thus, the probability of genotype AA is (1 – F) · p 2 + F · p, where the first term corresponds to the conditional probability that the person is AA given it is not inbred (p 2), multiplied by the prior probability that it is not inbred (1 − F), and the second term corresponds to the probability that a person is AA given it is inbred (p), multiplied by the probability that the person is inbred (F). This computation can be easily done for all genotypic classes leading to the expression for HWE under inbreeding:

(2) P ( A A ) = ( 1 − F ) · p 2 + F · p = p 2 + p · q · F P ( A B ) = ( 1 − F ) · 2 · p · q + F · 0 = 2 · p · q · ( 1 − F ) P ( B B ) = ( 1 − f ) · q 2 + F · q = q 2 + p · q · F

How much is inbreeding expected to modify genotypic distribution in human populations and what is the power to detect deviation from HWE due to inbreeding? The levels of inbreeding observed in human genetically isolated populations typically vary between 0.001 (low inbreeding) to 0.05 (relatively high) (see Rudan et al. [1], Pardo et al. [2]). To perform power estimation, we need to estimate the expectation of the χ2 statistics (the non-centrality parameter, NCP) used to test for HWE under the alternative hypothesis of deviation from HWE because of inbreeding. The test for HWE is performed using standard formula:

(3) T 2 = ∑ i ( O i − E i ) 2 E i

where summation is performed over all classes (genotypes); Oi is the count observed in the ith class, and Ei is the count expected under the null hypothesis (HWE). Under the null hypothesis, this test statistic is distributed as χ2 with number of degrees of freedom equal to the number of genotypes minus the number of alleles.

In our case, when we want to compute the expected value of the test under an alternative hypothesis, we use expectations of counts in different genotypic classes as "observed" values. Thus the expectation of this test statistic for some q, F, and N (sample size) is:

(4) E [ T 2 ] = ( N ( q 2 + p q F ) − N q 2 ) 2 N q 2 + ( N 2 p q ( 1 − F ) − N 2 p q ) 2 N 2 p q + ( N ( p 2 + p q F ) − N p 2 ) 2 N p 2 = ( N p q F ) 2 N q 2 + ( − 2 N p q F ) 2 N 2 p q + ( N p q F ) 2 N p 2 = N p 2 F 2 + 2 N p q F 2 + N q 2 F 2 = N F 2 ( p 2 + 2 p q + q 2 ) = N · F 2

Interestingly, the non-centrality parameter does not depend on the allelic frequency. Given the non-centrality parameter, it is easy to compute the power to detect deviation from HWE for any given F. For example, to achieve the power of >0.8 at α = 0.05, for a test with one degree of freedom, the non-centrality parameter should be >7.85. Thus, if F = 0.05, to have 80% power, N F 2 > 7.85, that is the required sample size should be N > 7.85 F 2 = 7.85 0.0025 = 3140 people.

Thus, even in populations with strong inbreeding, rather large sample sizes are required to detect the effects of inbreeding on HWE at a particular locus, even at a relatively weak significance level of 5%.

While the chance that deviation from HWE due to inbreeding will be statistically significant is relatively small, inbreeding may have clear effects on the results of HWE testing in GWA studies. Basically, if testing is performed at a threshold corresponding to nominal significance α, a proportion of markers which show significant deviation will be larger than α. Clearly, how large this proportion will be depends on the inbreeding and on size of the study – expectation of T 2 is a function of both N an F. A proportion of markers showing significant deviation from HWE at different values of inbreeding, sample size, and nominal significance threshold is shown in Table 9.1. While deviation of this proportion from nominal one is minimal at large αs, small sample sizes and coefficients of inbreeding, it may be 10-fold and even 100-fold higher than the nominal level at reasonable values of N and F for smaller thresholds.

TABLE 9.1. Expected Proportion of Markers Deviating from HWE in a Sample of N People Coming from a Population with Average Inbreeding F. Proportion of Markers is Shown for Particular Test Statistic Threshold, Corresponding to Nominal Significance α

α
N F 0.05 10−4 5·10−8
0.001 0.0501 1.008·10−4 5.077·10−8
1,000 0.005 0.0529 1.205·10−4 7.025·10−8
0.010 0.0615 1.885·10−4 14.503·10−8
0.001 0.0511 1.081·10−4 5.784·10−8
10,000 0.005 0.0790 3.544·10−4 36.991·10−8
0.010 0.1701 19.231·10−4 426.745·10−8

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Molecular Markers

Avinash Marwal , ... R.K. Gaur , in Animal Biotechnology, 2014

Applications of RAPD

Inbreeding indicates the degree of homozygosity at a locus within a population. Normally inbreeding is estimated in terms of a coefficient calculated from the pedigree of an individual. If no history is available, however, there is no way to estimate the inbreeding coefficient. Sometimes data on individuals are missing, and that too can prevent the estimation of the inbreeding coefficient, which is essential for formulation of a breeding program at the farm level and for breed development. Random amplified polymorphic DNA (RAPD) analysis was carried out on 20 randomly selected animals of three Indian cattle breeds (namely Red Sindhi, Hariana, and Tharparkar) maintained at three farms: Central Cattle Breeding Farm, Chiplima, Orissa, India; Shree gaushala, Jind, Hariana, India; Central Cattle Breeding Farm, Lakhimpur-Kheri, U.P., India ( Bhattacharya et al., 2003).

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Incest, Inbreeding, and their Consequences

A.H. Bittles , in International Encyclopedia of the Social & Behavioral Sciences, 2001

Inbreeding describes unions between couples known to share at least one common ancestor. While now rare in most Western societies, 20 percent to over 50 percent of current marriages in regions such as North Africa, West, Central, and South Asia are between couples related as second cousins or closer. The term incest is generally applied to any sexual union closer than permissible under prevailing religious or legal norms, and most commonly to mating between first-degree relatives, i.e., father–daughter, mother–son, or brother–sister, who have 50 percent of their genes in common. Incest avoidance is observed in virtually all human societies, and according to the Westermarck hypothesis it can be explained in terms of negative imprinting against close associates of early childhood. The adverse biological outcomes associated with inbreeding are caused by the expression of detrimental recessive genes. The closer the biological relationship between parents, the greater the probability that their offspring will inherit identical copies of one or more mutant genes. Thus the offspring of incestuous matings are four times more likely to have inherited identical gene copies from each parent than children born to first cousins, with associated adverse effects that may include developmental delay, physical anomalies, and intellectual handicap.

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Pocket Gopher

M.Susan DeVries , in The Laboratory Rabbit, Guinea Pig, Hamster, and Other Rodents, 2012

Housing and Pair Selection

Breeding in captivity has been achieved by pairing scrotal males with receptive females (see above) in neutral locations (e.g., cage, terrarium, etc.). Some pairs are intolerant of one another and exhibit aggressive behavior (Schramm, 1961). Pairs that are tolerant usually copulate. Copulatory behavior can be performed by novel individuals (Schramm, 1961), but, it has been suggested that repeated introductions of potential pair members could increase breeding success (Andersen, 1978). Considering that olfactory cues could be important in coordinating reproduction in pocket gophers (DeVries, 2007), copulatory behavior might be stimulated by placing feces and urine of receptive females within the simulated tunnel systems of males. After reproductive attempts, pair members should be separated and returned to their individual tunnel systems.

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Autoimmune Orchitis and Autoimmune Oophoritis

Livia Lustig , ... Kenneth S.K. Tung , in The Autoimmune Diseases (Fifth Edition), 2014

Autoimmune Orchitis in the Dark Mink

Inbreeding of mink for a dark fur, co-selected male infertility in this seasonal breeder ( Tung et al., 1981), but also affects mink with other fur colors (Pelletier, 1986). There are two histopathologic patterns: one has massive granulomatous inflammation, and the other extensive germ cell loss with little inflammation. In the latter, antibodies to sperm acrosome form an immune complex, with IgG and complement C3 depositing in the basement membrane outside the Sertoli cell barrier (SCB). Interestingly, there is an association of autoimmune orchitis with abnormal hypothalamic-pituitary-testicular function since correction of the hormonal defect prevented testis pathology (Tung et al., 1984). A study by Pelletier et al. (2009) has critically analyzed the spermatogenic cycle in this seasonal breeder and provided evidence that defects in the regulatory clearance mechanisms favor the breakdown of self-tolerance during spontaneous autoimmune orchitis in mink.

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Neglected Factors in Pharmacology and Neuroscience Research

In Techniques in the Behavioral and Neural Sciences, 1994

In Summary

Inbreeding eliminates the genotypic variation between individuals of a specific strain. Inbred animals are therefore preferable in many experimental studies as their genotype is constant in and between laboratories. In contrast, outbred animals differ in genotype and have for this reasons less defined characteristics.

The responsiveness of experimental animals may vary widely between various animal types (between inbred strains and between outbred stocks). In fact this concerns, in general, phenotypic differences to which both genotype and environmental factors contribute. Genotypic differences between strains may for this reason be expressed differently in experimental responses through modulation by environmental factors. Nevertheless, the proper choice of the inbred strain to be used, offers the best opportunity to select in a well defined way the most suitable phenotype. Verification of experimental results in several inbred strains offers a good possibility to judge their general validity.

As the type of animals used in experimental studies is a major variable in determining experimental results, in all publications animals must be identified by their strain or by their breeding system.

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