adequate folate levels is associated with a 72% reduction in NTDs, which is the most common class of human birth defects (Group MVSR and MRC Vitamin Study Research Group, 1991). This is due to the direct action of folate on the normalization of neural tube development due to its role in the division of rapidly dividing cells (Fleming and Copp, 1998; Blom et al., 2006). Folate deficiency also impairs nucleotide excision repair, which is the primary mechanism for removing UVR-induced DNA photoproducts (Han et al., 2007).
Competition for folate can be severe, especially when the body is stressed by UVR exposure and insufficient dietary folate. Recent research has demonstrated that folate regulates melanin production because it is required for the synthesis of GTP, which is a substrate for de novo production of tetrahydrobiopterin (BH4) and 6BH4 in melanocytes and keratinocytes (Shi et al., 2004; Schallreuter et al., 2008). The 6BH4 in turn regulates tyrosinase activity in the melanosome (Schallreuter, 2007). Because of the manifold importance of folate and its derivatives in cell division, DNA repair, and melanin production, and because of the sensitivity of these compounds to breakdown by UVR and ROS, natural selection to protect folate levels has been intense. Maintaining the integrity of folate metabolism has a high evolutionary valence because it directly affects reproductive success and survival early in life. The mechanisms operating to prioritize the utilization of folate under conditions of environmental and cellular stress caused by high UVR levels are not yet known.
The near absence in African populations of functionally significant variation in the coding region of the melanocortin 1 receptor (MC1R), one of the major genes regulating human eumelanin production, indicates the action of purifying selection maintaining dark pigmentation under intense selective pressure (Harding et al., 2000; John et al., 2003; Makova and Norton, 2005). The evidence of functional constraint on MC1R in African populations is unusual in light of the high levels of polymorphism observed at other loci in African populations (Makova and Norton, 2005). Evidence is mounting that darkly pigmented skin, or the potential for facultative development of dark pigmentation through tanning, evolved secondarily under positive selection in populations moving from low- to high-UVR environments. Pigmentary changes such as these appear to have occurred following the dispersal of lightly and moderately pigmented “Ancestral North Indians” into high-UVR reaches of the Indian subcontinent (Reich et al., 2009) and in lightly and moderately pigmented east Asians moving into the high-UVR environments of Central and mountainous South America (Bonilla et al., 2005). Further study of the genomic signatures of selection on pigmentation genes in human population is much needed.
The evolution of light pigmentation at high latitudes has long been related to the significance of production of vitamin D in the skin under