Snæbjörn Pálsson

Genetic determinants of hair, eye and skin pigmentation in Europeans

Hair, skin and eye colors are highly heritable and visible traits in humans. We carried out a genome-wide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun and freckling among 2,986 Icelanders. We then tested the most closely associated SNPs from six regions—four not previously implicated in the normal variation of human pigmentation—and replicated their association in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. The SNPs from all six regions met the criteria for genome-wide significance. A variant in SLC24A4 is associated with eye and hair color, a variant near KITLG is associated with hair color, two coding variants in TYR are associated with eye color and freckles, and a variant on 6p25.3 is associated with freckles. The fifth region provided refinements to a previously reported association in OCA2, and the sixth encompasses previously described variants in MC1R.

Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution

We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%–28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapBT2D, to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.

Two newly identified genetic determinants of pigmentation in Europeans.

We present results from a genome-wide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. Two coding variants in TPCN2 are associated with hair color, and a variant at the ASIP locus shows strong association with skin sensitivity to sun, freckling and red hair, phenotypic characteristics similar to those affected by well-known mutations in MC1R.

An Association Between the Kinship and Fertility of Human Couples

Previous studies have reported that related human couples tend to produce more children than unrelated couples but have been unable to determine whether this difference is biological or stems from socioeconomic variables. Our results, drawn from all known couples of the Icelandic population born between 1800 and 1965, show a significant positive association between kinship and fertility, with the greatest reproductive success observed for couples related at the level of third and fourth cousins. Owing to the relative socioeconomic homogeneity of Icelanders, and the observation of highly significant differences in the fertility of couples separated by very fine intervals of kinship, we conclude that this association is likely to have a biological basis.

Extensive sharing of chloroplast haplotypes among European birches indicates hybridization among Betula pendula, B. pubescens and B. nana

Extensive sharing of chloroplast haplotypes among the silver birch, Betula pendula Roth., the downy birch, B. pubescens Ehrh., and the dwarf birch, B. nana L., was discovered using polymerase chain reaction–restriction fragment length polymporphism markers. The geographical component of the genetic variation was stronger than the species component: the species were not significantly different while 11% of the variation could be attributed to differentiation between the two main regions studied, Scandinavia and western Russia. All haplotypes occurring in more than 2% of the individuals were shared among the species and the introgression ratios were quite large: 0.79 between B. pubescens and B. pendula and 0.67 between B. pubescens and B. nana. The data also indicate that B. pendula individuals are more similar to sympatric B. pubescens than to B. pendula individuals from nearby forests. However, this trend is not as pronounced when B. pubescens is considered, suggesting that introgression is not symmetrical. The haplotype sharing among the three Betula species is most likely caused by hybridization and subsequent cytoplasmic introgression.

Mitochondrial cytochrome b DNA sequence variation of Atlantic cod Gadus morhua, from Norway

We studied sequence variation of a fragment of the mitochondrial cytochrome b gene using polymerase chain reaction (PCR) and direct sequencing among 85 Norwegian Atlantic cod Gadus morhua, from nine sampling localities representing three overall areas: arctic, coastal and middle. In the analysis we include an additional 15 cod studied by Carr & Marshall (1991a). Nine base changes were found among the 100 sequences defining 11 haplotypes which differ from each other by one to five mutations. Two sites have been hit twice. All but one mutation are at third position silent sites. The variation passes several neutral‐theory tests and is thus suitable as marker for studying population differentiation. Coefficients of coancestry or intraclass correlation coefficient are negative both at the level of individuals within localities and localities within areas. This implies greater differences among individuals within populations than between populations. Intralocality nucleotide diversity is high and masks interlocality nucleotide divergence such that the net interlocality nucleotide divergence is nil. Similarly the net interarea nucleotide divergence is nil.

The impact of divergence time on the nature of population structure: an example from Iceland.

The Icelandic population has been sampled in many disease association studies, providing a strong motivation to understand the structure of this population and its ramifications for disease gene mapping. Previous work using 40 microsatellites showed that the Icelandic population is relatively homogeneous, but exhibits subtle population structure that can bias disease association statistics. Here, we show that regional geographic ancestries of individuals from Iceland can be distinguished using 292,289 autosomal single-nucleotide polymorphisms (SNPs). We further show that subpopulation differences are due to genetic drift since the settlement of Iceland 1100 years ago, and not to varying contributions from different ancestral populations. A consequence of the recent origin of Icelandic population structure is that allele frequency differences follow a null distribution devoid of outliers, so that the risk of false positive associations due to stratification is minimal. Our results highlight an important distinction between population differences attributable to recent drift and those arising from more ancient divergence, which has implications both for association studies and for efforts to detect natural selection using population differentiation.

Microsatellite variation in Daphnia pulex from both sides of the Baltic Sea.

Despite large genetic differentiation among neighbouring populations of many freshwater zooplankton species, a macrogeographical homogeneity of allozyme variation is generally observed. A study on breeding systems in Scandinavian populations of Daphnia pulex suggested a latitudinally related cline in breeding system with both diploid cyclic parthenogens and diploid obligate parthenogens at the latitude of 60–61°N. Variation at neutral markers may be more affected by selection at linked loci in such species than in strictly sexual species. In this paper I present a study of variation at five microsatellite loci in a total of 34 populations from small ponds and rockpools on both sides of the Baltic Sea at 60–61°N. Two major groups, which may represent different species of the D. pulex complex, are defined with the microsatellites. Neighbouring populations show both similar and well differentiated genetic composition. Populations separated by larger geographical distances show only a large differentiation and a macrogeographic pattern. The large differentiation observed at small distances can be explained with small effective population size: variation at the microsatellite loci has been shaped by population bottlenecks followed with expansion in size, and possibly by selection. No conclusive evidence is found for obligative parthenogenesis.

Associative overdominance, heterozygosity and fitness

Our aim in this study was to examine the power of associative overdominance in creating a correlation between individual heterozygosity and fitness and in maintaining genetic polymorphism at neutral loci. This was undertaken by simulating a diploid model with five chromosomes, each with 1000 loci that could have deleterious mutations linked to neutral markers located on the same chromosomes. The simulations were carried out with various combinations of the following parameters: population size (N), number of crossovers (c), selection coefficient (s) and dominance (h). All combinations of parameter values resulted in a positive regression of the fitness on the individual marker heterozygosity, although the fitness differences were not very large when c=2. The association between individual heterozygosity and fitness was clearest for recessive mutations (small h) with intermediate selection coefficients in small populations. The level of marker heterozygosity in the population was higher than the neutral expectation for many parameter values, even though regression of fitness on heterozygosity was not always steep at the individual level. These results agreed with the conclusion that associative overdominance could help to maintain polymorphisms in small populations. Strong selection occasionally yielded gene diversities lower than the neutral expectation, reflecting the prediction that strong selection reduces the effective population size.

A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries

Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease.