The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic.

OBJECTIVES: The C282Y allele is the major cause of hemochromatosis as a result of excessive iron absorption. The mutation arose in continental Europe no earlier than 6,000 years ago, coinciding with the arrival of the Neolithic agricultural revolution. Here we hypothesize that this new Neolithic diet, which originated in the sunny warm and dry climates of the Middle East, was carried by migrating farmers into the chilly and damp environments of Europe where iron is a critical micronutrient for effective thermoregulation. We argue that the C282Y allele was an adaptation to this novel environment. MATERIALS AND METHODS: To address our hypothesis, we compiled C282Y allele frequencies, known Neolithic sites in Europe and climatic data on temperature and rainfall for statistical analysis. RESULTS: Our findings indicate that the geographic cline for C282Y frequency in Europe increases as average temperatures decrease below 16°C, a critical threshold for thermoregulation, with rainy days intensifying the trend. DISCUSSION: The results indicate that the deleterious C282Y allele, responsible for most cases of hemochromatosis, may have evolved as a selective advantage to culture and climate during the European Neolithic.

Hemochromatosis: Niche Construction and the Genetic Domino Effect in the European Neolithic.

Hereditary hemochromatosis is caused by a potentially lethal recessive gene (HFE, C282Y allele) that increases iron absorption and reaches polymorphic levels in northern European populations. Because persons carrying the allele absorb iron more readily than do noncarriers, it has often been suggested that HFE is an adaptation to anemia. We hypothesize positive selection for HFE began during or after the European Neolithic with the adoption of an iron-deficient high-grain and dairying diet and consequent anemia, a finding confirmed in Neolithic and later European skeletons. HFE frequency compared with rate of lactase persistence in Eurasia yields a positive linear correlation coefficient of 0.86. We suggest this is just one of many mutations that became common after the adoption of agriculture.

Ultrasonographic measures of synovitis in an early phase clinical trial: a double-blind, randomised, placebo and comparator controlled phase IIa trial of GW274150 (a selective inducible nitric oxide synthase inhibitor) in rheumatoid arthritis.

OBJECTIVES: To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA). METHODS: A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area. RESULTS: At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). CONCLUSIONS: This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.

Early motherhood, high mortality, and HIV/AIDS rates in Sub-Saharan Africa.

Despite billions of dollars devoted to HIV/AIDS prevention since 1990, rates of infection continue to climb worldwide, primarily through heterosexual contact, and Sub-Saharan Africa is the worst case scenario (UNAIDS, 2004). Traditional intervention programs based on the ABCs (abstinence, being faithful, and condom use) of safe sex practices have shown mixed success. Engaging in risky sexual behavior (behaviors not adhering to the ABCs of safe sex practices) continues to escalate the HIV/AIDS epidemic. Although research abounds with correlates to HIV/AIDS rates, few studies have addressed the basis of sexual behavior. Here we show that not only are HIV/AIDS rates significantly higher in Sub-Saharan Africa than in the rest of the world but also infant mortality rates and teenage birth rates are higher as well. Based on these findings, we argue that engaging in risky sexual behavior, in many circumstances associated with deplorable living conditions and high mortality, is the only viable option for avoiding reproductive failure: dying without leaving surviving descendents. We suggest that initiatives that improve overall health and living conditions in the at-risk populations are necessary before traditional intervention programs can effectively combat the spread of HIV/AIDS in Sub-Saharan Africa.

The effects of kin propinquity on infant mortality.

This study tests the grandmother hypothesis and analyzes the effect of kin propinquity on infant mortality in a 19th century American frontier communal, polygynous population. The study shows that the presence of maternal grandmothers, aunts, uncles, and paternal aunts were significantly associated with increased infant survivorship while grandfathers, paternal grandmothers, and paternal uncles showed little effect. This study has implications for understanding the evolution of a long postreproductive life span, postmarital residential strategies, and behavioral strategies that enhance inclusive fitness.