Human-specific derived alleles of CD33 and other genes protect against postreproductive cognitive decline

Abstract

The individuals of most vertebrate species die when they can no longer reproduce. Humans are a rare exception, having evolved a prolonged postreproductive lifespan. Elders contribute to cooperative offspring care, assist in foraging, and communicate important ecological and cultural knowledge, increasing the survival of younger individuals. Age-related deterioration of cognitive capacity in humans compromises these benefits and also burdens the group with socially costly members. We investigated the contribution of the immunoregulatory receptor CD33 to a uniquely human postreproductive disease, Alzheimer’s dementia. Surprisingly, even though selection at advanced age is expected to be weak, a CD33 allele protective against Alzheimer’s disease is derived and unique to humans and favors a functional molecular state of CD33 resembling that of the chimpanzee. Thus, derived alleles may be compensatory and restore interactions altered as a consequence of human-specific brain evolution. We found several other examples of derived alleles at other human loci that protect against age-related cognitive deterioration arising from neurodegenerative disease or cerebrovascular insufficiency. Selection by inclusive fitness may be strong enough to favor alleles protecting specifically against cognitive decline in postreproductive humans. Such selection would operate by maximizing the contributions of postreproductive individuals to the fitness of younger kin.

Genomic evidence for the evolution of human postmenopausal longevity

“…In PNAS, Flavio Schwarz et al, in the laboratories of Ajit Varki and Pascal Gagneux at the University of California, San Diego/Salk Institute Center for Academic Research and Training in Anthropogeny (CARTA), report an apparent genetic signature of past selection for persistent cognitive competence at postfertile ages in humans (1). This can seem surprising because evolutionary explanations for aging (senescence) and its varying rates across species begin with the declining force of natural selection across adulthood (2).…”

“…The same scenario could account for polymorphisms of the APOE gene, which encodes for the plasma protein APOE, where the allele that is derived in humans is also protective against the latelife onset of Alzheimer's disease (13,14). Schwarz et al also suggest that as expanded capacities to transmit information evolved with human language, competent elders of both sexes became especially valuable to both kin and community (1).…”

“…Those "hard" lines of evidence-stone tools with cut-marked bones of large animals and increased cranial capacity in genus Homo-have long made meat eating and brain size favored candidates to explain the evolution of our longevity (14). Schwarz et al's demonstration (1) shows that genomics offers a line of evidence into the character and timing of life history shifts that might themselves have been the crucial foundation for many distinctively human features (15,16). Although the authors found the derived CD33 allele only in modern humans, the small number of Neanderthal and Denisovan genomes currently available cannot rule out similar polymorphisms in those taxa.…”

“…Although the authors found the derived CD33 allele only in modern humans, the small number of Neanderthal and Denisovan genomes currently available cannot rule out similar polymorphisms in those taxa. Schwarz et al (1) note that both the global distribution and apparent absence of recent selection in the CD33, APOE, and other derived protective alleles indicate they evolved before modern humans emerged in Africa. How long before might eventually be revealed by statistical methods yet to be developed (1).…”

“…Schwarz et al (1) note that both the global distribution and apparent absence of recent selection in the CD33, APOE, and other derived protective alleles indicate they evolved before modern humans emerged in Africa. How long before might eventually be revealed by statistical methods yet to be developed (1).…”