title: 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.
authors.affiliation: Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, CA 92093; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Flavio
authors.initials: F
authors.lastname: Schwarz
authors.affiliation: Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, CA 92093; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Stevan A
authors.initials: SA
authors.lastname: Springer
authors.affiliation: Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, CA 92093; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Tasha K
authors.initials: TK
authors.lastname: Altheide
authors.affiliation: Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, CA 92093; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; Department of Pathology, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Nissi M
authors.initials: NM
authors.lastname: Varki
authors.affiliation: Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, CA 92093; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; Department of Pathology, University of California, San Diego, La Jolla, CA 92093 a1varki@ucsd.edu pgagneux@ucsd.edu.
authors.forename: Pascal
authors.initials: P
authors.lastname: Gagneux
authors.affiliation: Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, CA 92093; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093; a1varki@ucsd.edu pgagneux@ucsd.edu.
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D005075:Biological Evolution; D001921:Brain / Q000503:physiopathology*; D002561:Cerebrovascular Disorders / Q000235:genetics; D003072:Cognition Disorders / Q000235:genetics*; D005298:Fertility / Q000235:genetics; D056084:Genetic Fitness; D056426:Genetic Loci; D006801:Humans; D002679:Pan troglodytes; D012641:Selection, Genetic; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; C571163:CD33 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3
keywords: Alzheimer’s disease; CD33; Siglec; cognitive capacity; postreproductive lifespan