Homozygosity and risk of childhood death due to invasive bacterial disease

The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
BMC Medical Genetics (Impact Factor: 2.08). 07/2009; 10(1):55. DOI: 10.1186/1471-2350-10-55
Source: PubMed


Genetic heterozygosity is increasingly being shown to be a key predictor of fitness in natural populations, both through inbreeding depression, inbred individuals having low heterozygosity, and also through chance linkage between a marker and a gene under balancing selection. One important component of fitness that is often highlighted is resistance to parasites and other pathogens. However, the significance of equivalent loci in human populations remains unclear. Consequently, we performed a case-control study of fatal invasive bacterial disease in Kenyan children using a genome-wide screen with microsatellite markers.
148 cases, comprising children aged <13 years who died of invasive bacterial disease, (variously, bacteraemia, bacterial meningitis or neonatal sepsis) and 137 age-matched, healthy children were sampled in a prospective study conducted at Kilifi District Hospital, Kenya. Samples were genotyped for 134 microsatellite markers using the ABI LD20 marker set and analysed for an association between homozygosity and mortality.
At five markers homozygosity was strongly associated with mortality (odds ratio range 4.7 - 12.2) with evidence of interactions between some markers. Mortality was associated with different non-overlapping marker groups in Gram positive and Gram negative bacterial disease. Homozygosity at susceptibility markers was common (prevalence 19-49%) and, with the large effect sizes, this suggests that bacterial disease mortality may be strongly genetically determined.
Balanced polymorphisms appear to be more widespread in humans than previously appreciated and play a critical role in modulating susceptibility to infectious disease. The effect sizes we report, coupled with the stochasticity of exposure to pathogens suggests that infection and mortality are far from random due to a strong genetic basis.

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Available from: Charles Newton, Oct 10, 2015
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    • "Anne Elizabeth most likely died of child tuberculosis (Keynes, 2001; Fenner, Egger & Gagneux, 2009) and Charles Waring died of scarlet fever (Burhardt & Smiths, 1991); recent evidence also reveals that inbreeding is an important risk factor in susceptibility to infectious diseases such as tuberculosis and hepatitis (Lyons et al., 2009b). In addition, an association between homozygosity and childhood mortality resulting from invasive bacterial disease has been also reported (Lyons et al., 2009a). The evidence of inbreeding depression on child survival in Charles Darwin's offspring together with the findings reported in the present study of an adverse effect of inbreeding on fertility in his sons suggest that Darwin's fears on the health of his children as a result of his marriage with his first cousin Emma Wedgwood were neither unjustified nor exaggerated. "
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    ABSTRACT: Charles Darwin, who was married to his first cousin Emma Wedgwood, was the first experimentalist to demonstrate the adverse effects of inbreeding. He documented the deleterious consequences of self-fertilization on progeny in numerous plant species, and this research led him to suspect that the health problems of his 10 children, who were very often ill, might have been a consequence of his marriage to his first cousin. Because Darwin’s concerns regarding the consequences of cousin marriage on his children even nowadays are considered controversial, we analyzed the potential effects of inbreeding on fertility in 30 marriages of the Darwin–Wedgwood dynasty, including the marriages of Darwin’s children, which correspond to the offspring of four cousin marriages and three marriages between unrelated individuals. Analysis of the number of children per woman through zero-inflated regression models showed a significantly adverse effect of the husband inbreeding coefficient on family size. Furthermore, a statistically significant adverse effect of the husband inbreeding coefficient on reproductive period duration was also detected. To our knowledge, this is the first time that inbreeding depression on male fertility has been detected in humans. Because Darwin’s sons had fewer children in comparison to non-inbred men of the dynasty, our findings give empirical support to Darwin’s concerns on the consequences of consanguineous marriage in his own progeny
    Biological Journal of the Linnean Society 11/2014; 114(2). DOI:10.1111/bij.12433 · 2.26 Impact Factor
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    • "reas heterozygosity is associated with immune advantages ( e . g . Acevedo - Whitehouse et al . , 2005 ; Keller and Waller , 2002 ; Lie et al . , 2009 ; Lyons et al . , 2009a ; MacDougall - Shackleton et al . , 2005 ) . In humans , for example , homozygosity is associated with elevated risks of tuberculosis , hepatitis , and bacterial meningitis ( Lyons et al . , 2009a , 2009b ) . The health advantages of genetic het - erozygosity are apparently not just limited to infectious diseases , as several studies have demonstrated an association between homozygosity and increased susceptibility to degenerative dis - eases in humans such as hypertension , high cholesterol , and cancer ( Lie et al . , 2009 ; Be"
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    ABSTRACT: Eight years ago, Ramenofsky et al. (2003) characterized the discussion of the impact of Old World diseases on Native American populations as almost exclusively historical in nature. They specifically argued for the application of more evolutionary, genetic, and epidemiological theory to research into this topic. We agree with their assessment and further suggest that such research would greatly benefit from spatial analyses of disease spread as well. Using trend surface analysis of existing ethnohistorical and archaeological data pertaining to population sizes and disease events, we examine the spatiotemporal dimensions of 17th century depopulation in northeastern North America. The subsequent results allow us to predict possible depopulation rates for populations with very little demographic data. Further, our use of biological, historical, and cultural data to interpret the results represents an attempt to provide a more complex explanation for the variability in cultural survivability across the region and several possible avenues for productive future research. We believe research like this can significantly improve our understanding of how Old World diseases affected historic Native American populations and cultures and continue to impact them today.
    Journal of Anthropological Archaeology 03/2012; 31(1). DOI:10.1016/j.jaa.2011.10.004 · 2.32 Impact Factor
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    • "Notably, most of the loci that deviated from H-WE revealed high F-values and a tendency towards homozygosity, thus enhancing their dominance in eri subpopulations. High homozygosity, homogeneous distribution and the high survival rate exerted a positive influence on genes favorable for fitness, thus confirming the significant association between alleles and fitness traits that contribute to the survival (Schulze and McMahon, 2002; Lyons et al., 2009) of eri populations under environmental stress (e.g. high altitudes), instead of high heterozygosity, which tends to be non-heritable. "
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    ABSTRACT: Deforestation and exploitation has led to the fragmentation of habitats and scattering of populations of the economically important eri silkworm, Samia cynthia ricini, in north-east India. Genetic analysis of 15 eri populations, using ISSR markers, showed 98% inter-population, and 23% to 58% intra-population polymorphism. Nei's genetic distance between populations increased significantly with altitude (R(2) = 0.71) and geographic distance (R(2) = 0.78). On the dendrogram, the lower and upper Assam populations were clustered separately, with intermediate grouping of those from Barpathar and Chuchuyimlang, consistent with geographical distribution. The Nei's gene diversity index was 0.350 in total populations and 0.121 in subpopulations. The genetic differentiation estimate (Gst) was 0.276 among scattered populations. Neutrality tests showed deviation of 118 loci from Hardy-Weinberg equilibrium. The number of loci that deviated from neutrality increased with altitude (R(2) = 0.63). Test of linkage disequilibrium showed greater contribution of variance among eri subpopulations to total variance. D('2)IS exceeded D('2)ST, showed significant contribution of random genetic drift to the increase in variance of disequilibrium in subpopulations. In the Lakhimpur population, the peripheral part was separated from the core by a genetic distance of 0.260. Patchy habitats promoted low genetic variability, high linkage disequilibrium and colonization by new subpopulations. Increased gene flow and habitat-area expansion are required to maintain higher genetic variability and conservation of the original S. c. ricini gene pool.
    Genetics and Molecular Biology 07/2011; 34(3):502-10. DOI:10.1590/S1415-47572011005000033 · 1.20 Impact Factor
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