Tasha K. Altheide

Initial sequence of the chimpanzee genome and comparison with the human genome

Here we present a draft genome sequence of the common chimpanzee (Pan troglodytes). Through comparison with the human genome, we have generated a largely complete catalogue of the genetic differences that have accumulated since the human and chimpanzee species diverged from our common ancestor, constituting approximately thirty-five million single-nucleotide changes, five million insertion/deletion events, and various chromosomal rearrangements. We use this catalogue to explore the magnitude and regional variation of mutational forces shaping these two genomes, and the strength of positive and negative selection acting on their genes. In particular, we find that the patterns of evolution in human and chimpanzee protein-coding genes are highly correlated and dominated by the fixation of neutral and slightly deleterious alleles. We also use the chimpanzee genome as an outgroup to investigate human population genetics and identify signatures of selective sweeps in recent human evolution.Here we present a draft genome sequence of the common chimpanzee (Pan troglodytes). Through comparison with the human genome, we have generated a largely complete catalogue of the genetic differences that have accumulated since the human and chimpanzee species diverged from our common ancestor, constituting approximately thirty-five million single-nucleotide changes, five million insertion/deletion events, and various chromosomal rearrangements. We use this catalogue to explore the magnitude and regional variation of mutational forces shaping these two genomes, and the strength of positive and negative selection acting on their genes. In particular, we find that the patterns of evolution in human and chimpanzee protein-coding genes are highly correlated and dominated by the fixation of neutral and slightly deleterious alleles. We also use the chimpanzee genome as an outgroup to investigate human population genetics and identify signatures of selective sweeps in recent human evolution.

System-wide genomic and biochemical comparisons of sialic acid biology among primates and rodents: Evidence for two modes of rapid evolution

Numerous vertebrate genes are involved in the biology of the oligosaccharide chains attached to glycoconjugates. These genes fall into diverse groups within the conventional Gene Ontology classification. However, they should be evaluated together from functional and evolutionary perspectives in a “biochemical systems” approach, considering each monosaccharide units biosynthesis, activation, transport, modification, transfer, recycling, degradation, and recognition. Sialic acid (Sia) residues are monosaccharides at the outer end of glycans on the cell-surface and secreted molecules of vertebrates, mediating recognition by intrinsic or extrinsic (pathogen) receptors. The availability of multiple genome sequences allows a system-wide comparison among primates and rodents of all genes directly involved in Sia biology. Taking this approach, we present further evidence for accelerated evolution in Sia-binding domains of CD33-related Sia-recognizing Ig-like lectins. Other gene classes are more conserved, including those encoding the sialyltransferases that attach Sia residues to glycans. Despite this conservation, tissue sialylation patterns are shown to differ widely among these species, presumably because of rapid evolution of sialyltransferase expression patterns. Analyses of N- and O-glycans of erythrocyte and plasma glycopeptides from these and other mammalian taxa confirmed this phenomenon. Sia modifications on these glycopeptides also appear to be undergoing rapid evolution. This rapid evolution of the sialome presumably results from the ongoing need of organisms to evade microbial pathogens that use Sia residues as receptors. The rapid evolution of Sia-binding domains of the inhibitory CD33-related Sia-recognizing Ig-like lectins is likely to be a secondary consequence, as these inhibitory receptors presumably need to keep up with recognition of the rapidly evolving “self”-sialome.

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

Significance Most vertebrates die soon after they stop reproducing, but humans are an exception. Postreproductive humans care for offspring, assist in foraging, and communicate ecological and cultural knowledge, increasing the survival of younger individuals. Loss of cognitive capacity disrupts these benefits and burdens the group with the care of older members. We studied how the immunoregulatory receptor CD33 contributes to Alzheimer’s disease, a human-specific postreproductive condition. Surprisingly, a protective CD33 allele is derived and unique to humans, despite weak direct selection on older individuals. We identified several genes with derived alleles that protect against neurodegenerative disease and cerebrovascular insufficiency in old age. Selection by inclusive fitness may be strong enough to favor alleles that protect against cognitive decline in postreproductive humans. 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.

SIGLEC12, a Human-specific Segregating (Pseudo)gene, Encodes a Signaling Molecule Expressed in Prostate Carcinomas

The primate SIGLEC12 gene encodes one of the CD33-related Siglec family of signaling molecules in immune cells. We had previously reported that this gene harbors a human-specific missense mutation of the codon for an Arg residue required for sialic acid recognition. Here we show that this R122C mutation of the Siglec-XII protein is fixed in the human population, i.e. it occurred prior to the origin of modern humans. Additional mutations have since completely inactivated the SIGLEC12 gene in some but not all humans. The most common inactivating mutation with a global allele frequency of 58% is a single nucleotide frameshift that markedly shortens the open reading frame. Unlike other CD33-related Siglecs that are primarily found on immune cells, we found that Siglec-XII protein is expressed not only on some macrophages but also on various epithelial cell surfaces in humans and chimpanzees. We also found expression on certain human prostate epithelial carcinomas and carcinoma cell lines. This expression correlates with the presence of the nonframeshifted, intact SIGLEC12 allele. Although SIGLEC12 allele status did not predict prostate carcinoma incidence, restoration of expression in a prostate carcinoma cell line homozygous for the frameshift mutation induced altered regulation of several genes associated with carcinoma progression. These stably transfected Siglec-XII-expressing prostate cancer cells also showed enhanced growth in nude mice. Finally, monoclonal antibodies against the protein were internalized by Siglec-XII-expressing prostate carcinoma cells, allowing targeting of a toxin to such cells. Polymorphic expression of Siglec-XII in humans thus has implications for prostate cancer biology and therapeutics.

Reply to Liu and Jiang: Maintenance of postreproductive cognitive capacity by inclusive fitness

Our paper examines genes influencing cognitive decline in postreproductive humans, which arises from neurodegenerative and cardiovascular disease (1). Among these polymorphic genes, we found many protective alleles that are derived from and are unique to the human lineage. Liu and Jiang (2) add an important observation about potential effects of some of these loci earlier in life. Data from three studies indicate that these genes do not influence cognitive performance during childhood (3) or in the general population (4, 5). Our paper (1) does not address early phenotypes, as the establishment of early cognitive function and protection against late degeneration need not involve the same … [↵][1]1To whom correspondence may be addressed. Email: a1varki{at}ucsd.edu or pgagneux{at}ucsd.edu. [1]: #xref-corresp-1-1