Biomedical subjects

Svante Paabo

Publications and source records attributed to Svante Paabo.

4 recordsLinked to original sources

PubMed2006

Structure of the forkhead domain of FOXP2 bound to DNA.

FOXP (FOXP1-4) is a newly defined subfamily of the forkhead box (FOX) transcription factors. A mutation in the FOXP2 forkhead domain cosegregates with a severe speech disorder, whereas several mutations in the FOXP3 forkhead domain are linked to the IPEX syndrome in human and a similar autoimmune phenotype in mice. Here we report a 1.9 A crystal structure of the forkhead domain of human FOXP2 bound to DNA. This structure allows us to revise the previously proposed DNA recognition mechanism and provide a unifying model of DNA binding for the FOX family of proteins. Our studies also reveal that the FOXP2 forkhead domain can form a domain-swapped dimer, made possible by a strategic substitution of a highly conserved proline in conventional FOX proteins with alanine in the P subfamily. Disease-causing mutations in FOXP2 and FOXP3 map either to the DNA binding surface or the domain-swapping dimer interface, functionally corroborating the crystal structure.

Amino Acid Sequence↗

PubMed2004

Comparative primate genomics.

With the completion of the human genome sequence and the advent of technologies to study functional aspects of genomes, molecular comparisons between humans and other primates have gained momentum. The comparison of the human genome to the genomes of species closely related to humans allows the identification of genomic features that set primates apart from other mammals and of features that set certain primates notably humans apart from other primates. In this article, we review recent progress in these areas with an emphasis on how comparative approaches may be used to identify functionally relevant features unique to the human genome.

Adaptation, Physiological↗

PubMed2003

Selection on human genes as revealed by comparisons to chimpanzee cDNA.

To better understand the evolutionary forces that affect human genes, we sequenced 5055 expressed sequence tags from the chimpanzee and compared them to their human counterparts. In conjunction with intergenic chimpanzee DNA sequences and data on human single-nucleotide polymorphisms in the genes studied, this allows us to gauge the extent to which selection affects human genes at a genome-wide scale. The comparison to intergenic DNA sequences indicates that about 39% of silent sites in protein-coding regions are deleterious and subject to negative selection. Further, when the divergence between human and chimpanzee is compared with the extent of nucleotide polymorphisms among humans in the same sequences, there is significantly higher divergence in the 5' untranslated regions (UTRs) but not in other parts of the transcript. This indicates that positive selection may have had a considerable influence on 5'UTRs. The dinucleotide CG (CpG) also exhibits a different substitution pattern within 5'UTRs as compared with other parts of the genome.

Amino Acid Substitution↗

PubMed2002

Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution.

Humans are genetically deficient in the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) because of an Alu-mediated inactivating mutation of the gene encoding the enzyme CMP-N-acetylneuraminic acid (CMP-Neu5Ac) hydroxylase (CMAH). This mutation occurred after our last common ancestor with bonobos and chimpanzees, and before the origin of present-day humans. Here, we take multiple approaches to estimate the timing of this mutation in relationship to human evolutionary history. First, we have developed a method to extract and identify sialic acids from bones and bony fossils. Two Neanderthal fossils studied had clearly detectable Neu5Ac but no Neu5Gc, indicating that the CMAH mutation predated the common ancestor of humans and the Neanderthal, approximately 0.5-0.6 million years ago (mya). Second, we date the insertion event of the inactivating human-specific sahAluY element that replaced the ancestral AluSq element found adjacent to exon 6 of the CMAH gene in the chimpanzee genome. Assuming Alu source genes based on a phylogenetic tree of human-specific Alu elements, we estimate the sahAluY insertion time at approximately 2.7 mya. Third, we apply molecular clock analysis to chimpanzee and other great ape CMAH genes and the corresponding human pseudogene to estimate an inactivation time of approximately 2.8 mya. Taken together, these studies indicate that the CMAH gene was inactivated shortly before the time when brain expansion began in humankind's ancestry, approximately 2.1-2.2 mya. In this regard, it is of interest that although Neu5Gc is the major sialic acid in most organs of the chimpanzee, its expression is selectively down-regulated in the brain, for as yet unknown reasons.

Animals↗