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Tests to demonstrate a preference by mosquitoes for stinging controls as opposed to obligate heterozygotes for Cystic Fibrosis proved negative. If a heterozygote advantage caused a lower malarial incidence in carriers in South West Africa, it must have worked through the malarial parasite being adversely affected by a serum factor. This remains to be tested.
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Cystic fibrosis is the most common lethal or semi-lethal genetic disease in Caucasians of Central European origin, among whom it is inherited as an autosomal recessive trait at a frequency approximately 10 times that expected from recurrent mutation alone. A decreased sialic acid content has been observed in cell surface glycoproteins on cystic fibrosis fibroblasts and in numerous soluble glycoprotein preparations from cystic fibrosis homozygotes. Sialic acid residues on cell surface glycoconjugates play an essential role in the binding and infectivity of myxoviruses and paramyxoviruses, including those causing pandemic influenza. It is suggested that increased resistance to these viruses conferred by similar but quantitatively smaller alterations in sialoglycoconjugate structure in cystic fibrosis heterozygotes may have provided a selective advantage to maintain the high frequency of the cystic fibrosis gene in Caucasian populations.
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Inbreeding depression is a widespread phenomenon that reflects the burden of deleterious effects hidden in heterozygosis in non-inbred populations but exposed in homozygosis in inbred individuals, known as inbreeding load (B). This load can be due to partially or fully recessive deleterious mutations (dominance model) or to heterozygote advantage (overdominance model, where both homozygotes are deleterious relative to the heterozygote). There are many studies addressing the changes in inbreeding load in finite populations assuming the dominance model. However, the contribution of overdominance to inbreeding depression has been focused on infinite-size populations. We carried out computer simulations to investigate the joint impact of dominant and pure overdominant mutations on inbreeding load, both for self-fertilizing populations and for panmictic populations suffering from a drastic bottleneck. We found that the overdominant inbreeding load can be substantially reduced by drift even for symmetrical overdominance, at least when considering mutations of small effect. For panmictic bottlenecked populations, the reduction in inbreeding load under dominance and overdominance loci cannot be easily distinguished. However, while purging depletes inbreeding load from dominant loci, slowing inbreeding depression and leading to partial fitness recovery, for overdominant loci fitness declines monotonically.
Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity, with immune dysregulation at the maternal-fetal interface central to its pathogenesis. The highly polymorphic HLA region mediates maternal immune tolerance of the semi-allogeneic fetus, yet the contribution of HLA diversity to PE risk remains poorly defined. Whether the HLA heterozygote advantage observed in other immune disorders is relevant to PE has not been systematically evaluated. Using data from the multi-ancestry TOPMed Boston-Colombia Collaborative for Adverse Pregnancy Outcomes (n = 12,790; 4770 PE, 8020 controls; 10,808 maternal, 1982 fetal, including 1848 pairs), we evaluated associations between heterozygosity across eight classical HLA loci and PE and four sub-phenotypes, adjusting for genetic ancestry. HLA heterozygosity was common across most loci (> 80%). No individual maternal HLA locus was associated with overall PE; however, heterozygosity across Class I loci showed a protective effect in preterm PE (OR = 0.81, 95% CI: 0.68-0.97), with a similar pattern for HLA-A heterozygosity (OR = 0.78, 95% CI: 0.64-0.97). In contrast, fetal heterozygosity at HLA-DQB1 was nominally associated with increased risk of PE (OR = 1.36, 95% CI: 1.03-1.80) and preterm PE (OR = 1.73, 95% CI: 1.13-2.74). No individual maternal or fetal HLA alleles were associated with PE. Maternal-fetal mismatch analysis demonstrated locus-specific associations with preterm PE, including increased risk with HLA-DQA1 mismatch and reduced risk with HLA-C mismatch. These findings highlight distinct maternal and fetal immunogenetic contributions to PE risk and underscore the importance of considering HLA diversity-rather than individual alleles alone-in studies of PE aetiology.
An allelic variant of the autophagy gene ATG16L1 (T300A) is a genetic risk factor for Crohn's disease. However, over 50% of the global population carries at least one copy. Yao et al. have demonstrated a heterozygote advantage, where the pathogen-protective effect of one allele may outweigh the disease risk in homozygotes.
The hand preferences of Open University (OU) students and their relatives, including children, are described. As in earlier series, estimates of heritability are higher for mothers than fathers. There is no evidence of smaller heritability for paternal than maternal grandparents. The distribution of left-handedness in families is examined in the light of predictions of the right shift theory and on the assumption that the shift depends on a single gene. Good agreement is found between the observed and expected numbers of R x R, L x R and L x L families. Predictions are successful for both strict and generous criteria of sinistrality. Generation differences are found between OU students and their parents and between the students and their children. These are discussed from the viewpoint of a possible heterozygote advantage in intelligence. The higher proportion of sinistral children born to sinistral mothers than fathers can be partly accounted for by supposing that the right shift is more effective in females than males.
In a study on genetic markers (22 HLA antigens, 6 blood group types, 3 serum groups and 3 red cell enzymes) in psoriatic patients the following statistically significant differences were found between patients and controls: 1) The HLA factors B13 and Bw17, the Lewis blood group Le(a-b-) and the blood group factor A were overrepresented among the patients. A decrease in the frequencies of the HLA factors B7 and B8 was noted, confirming several similar findings by other investigators. 2) In the Ss (MNSs), C3 and haptoglobin (Hp) systems the psoriatic patients showed a decreased frequency of heterozygotes. 3) Among patients with continuous symptoms the blood group factor A and the blood group Fy (a+b-) were overrepresented. 4) Patients with late onset of psoriasis showed an increase in the blood group (Fy(a+bb-) and a decrease in the haptoglobin type 2-2. Relative risk figures have been calculated for different phenotypes. Certain genetic combinations were found to be grossly overrepresented among the patients. The mechanisms behind the associations appear to differ. In three systems (Ss, C3 and Hp) the deviations in psoriatic patients suggest the presence of heterozygote advantage.
Human preferences can shape the genetic evolution of other species via conservation practices, public health actions, and domestication. While the dynamics of domestication have been explored in depth through empirical and theoretical analyses, few studies have analyzed models for the coevolution of human cultural preferences with the genetics of a domesticate population. Humans shape the fitness landscape of domesticate populations both intentionally and unconsciously, by selecting for desirable traits and modifying environments; in turn, changes in domesticate phenotypes can affect the cultural preferences in the domesticator population. We present a model for the dynamics of domestication which includes interactions between genetic evolution, cultural transmission, and selective pressures. The model includes forms of selection due to culturally transmitted domesticator preferences that can affect the dynamics of domesticate genetic variants, which then affect the dynamics of domesticators. Equilibria with simultaneous genetic and cultural polymorphisms may exist, and may occur under apparent heterozygote disadvantage in the domesticate. Stable quasiperiodic cycles in both domesticates and domesticators are also possible.
The alpha-galactosidase/beta-hexosaminidase ratio was measured for individual hair roots as a method for heterozygote detection in Fabry's disease. Hair root analysis in control individuals revealed no striking sex difference in alpha-galactosidase/beta-hexosaminidase ratio when five males and five females were compared. The values for the ratio X 100, calculating both enzyme activities in nmol of product per min per microliter of hair extract, ranged from 0.8 to 9 for controls and from less than 0.1 to 0.4 for two hemizygous males. Hair root analysis in four heterozygotes with clinical evidence of disease gave values for each individual in the control range, in the range for hemizygotes and in an intermediate range. The experience using hair root analysis for heterozygote detection in the X-linked Lesch-Nyhan syndrome suggests that this approch will be a sensitive heterozygote detection method which takes advantage of the occurrence of hairs with a deficient phenotype on the basis of Lyonization. We observed an affected male who was born to a female without clinical or biochemical evidence (examination included extensive hair root analysis) of Fabry's disease, thus documenting a likely instance of new mutation.
The kinetics of sickling of malaria-infected red cells from humans with sickle cell trait were studied in vitro in an attempt to obtain direct experimental evidence for a selective advantage of the hemoglobin S heterozygote in a malarious region. The sickling rates of cells infected with Plasmodium falciparum and of non-infected cells were studied both in the total absence of oxygen (by dithionite addition) and at several different concentrations of oxyhemoglobin which might obtain in vivo. In all cases, red cells containing small plasmodium parasite forms (ring forms) sickled approximately eight times as readily as uninfected cells. Cells containing large parasitic forms (trophozoites and schizonts) appeared to sickle less readily than uninfected cells, by light microscopy criteria, but electron micrographs demonstrated the presence of polymerized deoxyhemoglobin S with a high frequency. It is concluded that enhanced sickling of plasmodium-infected AS cells may be one mechanism whereby the hemoglobin S polymorphism is balanced in favor of the heterozygote.
The high frequencies of the Hb S and G6PD-deficiency genes in the tropics are explained by their relative resistance against malarial infection. They may confer advantage through lower infection rates or through lower parasitaemia. There is evidence that heterozygote carriers of these genes are partially protected. The mechanism of resistance is known for Hb S but not completely understood for the G6PD-deficiency gene. Other red cell factors are discussed with respect to innate resistance against malaria.
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Metachromatic leukodystrophy and Maroteaux-Lamy syndrome can be diagnosed by assay of leukocyte or fibroblast arylsulfatase A and B activity with the fluorogenic substrate 4-methylumbelliferyl sulfate. The arylsulfatases are extracted into a 27000 x g supernatant by sonication in 0.9% sodium chloride and then separated with CM-32 on columns or in test tubes. In 0.05 M sodium acetate pH 6.0, arylsulfatase A is not absorbed while arylsulfatase B is retained by the resin. The arylsulfatase B is then eluted from the resin with 0.3 M sodium chloride. The arylsulfatase A activity obtained from normal leukocytes and fibroblasts is linear for the initial 10 minutes of the reaction, is stimulated 3-fold by 6 mM lead acetate and inhibited 80% by 0.24 mM silver nitrate. After separation with CM-32, the arylsulfatase B activity is stimulated 3-fold by Triton X-100 (0.1%). Arylsulfatase A but not arylsulfatase B is destroyed by heat (60 degrees). Both leukocyte and fibroblast arylsulfatase A activity was reduced to 11% of control values in metachromatic leukodystrophy. Essentially no arylsulfatase B activity was detected in cells from patients with Maroteaux-Lamy syndrome. Metachromatic leukodystrophy heterozygotes but not Maroteaux-Lamy syndrome heterozygotes can also be distinguished by this method. A heat inactivation technique utilizing the differential thermal stabilities of the two enzymes for diagnosis of patients with Marotezux-Lamy syndrome is also described. The advantages of these 4-methylumbelliferyl sulfate assay procedures over the p-nitrocatechol sulfate method of assay are greater sensitivity, selectivity for the desired enzyme and potential for use in large scale testing.
In a clinical study, 702 Nigerian children aged 1-6 years were examined for malaria. Comparison of morbidity rates and parasitemia of patients with different glucose-6-phosphate dehydrogenase (G6PD) status provided evidence that in heterozygous females the gene for G6PD deficiency (GdA-/GdB) confers an advantage against malaria.
The prevalence of different haemoglobins and their interaction with malaria have been studied in Garki, Kano State, Nigeria. Sickle cell trait was present in 24% of newborn and 29% of those aged over five years. Hb.AC was present in 0.7%. Frequency of both haemoglobin variants was greater in Hausa than Fulani. Sickle cell anaemia was almost invariably fatal in early childhood. The distribution curve of percentage of Hb.S in sickle cell trait subjects was normal, and did not demonstrate any high frequency of a gene for alpha-thalassaemia. The presence of beta-thalassaemia minor could not be tested, but Hb.S/beta-thalassaemia was not detected. Hb.S gene frequency appears to have been maintained by a fitness in heterozygotes of 21% over normal homozygotes; increased fertility and high mutation rate did not make any apparent contribution. Hb.AS subjects had on average lower frequency and considerably lower densities of Plasmodium falciparum trophozoites than Hb.AA from the age of 30 to 59 weeks; density was less in sickle cell trait up to age three years in the dry season only. It is suggested that the survival advantage and hence the prevalence of sickle cell trait may be greatest in some hyperendemic areas and less where malaria transmission is extremely high or when it is high and unvaried.