Changing the name of the NBPF/DUF1220 domain to the Olduvai domain

We are jointly proposing a new name for a protein domain of approximately 65 amino acids that has been previously termed NBPF or DUF1220. Our two labs independently reported the initial studies of this domain, which is encoded almost entirely within a single gene family. The name Neuroblastoma Breakpoint Family (NBPF) was applied to this gene family when the first identified member of the family was found to be interrupted in an individual with neuroblastoma. Prior to this discovery, the PFAM database had termed the domain DUF1220, denoting it as one of many protein domains of unknown function. It has been PFAM’s intention to use “DUF” nomenclature to serve only as a temporary placeholder until more appropriate names are proposed based on research findings. We believe that additional studies of this domain, primarily from our laboratories over the past 10 years, have resulted in furthering our understanding of these sequences to the point where proposing a new name for this domain is warranted. Because of considerable data linking the domain to human-specific evolution, brain expansion and cognition, we believe a name reflecting these findings would be appropriate. With this in mind, we have chosen to name the domain (and the repeat that encodes it) Olduvai. The gene family will remain as NBPF for now. The primary domain subtypes will retain their previously assigned names (e.g. CON1-3; HLS1-3), and the three-domain block that expanded dramatically in the human lineage will be termed the Olduvai triplet. The new name refers to Olduvai Gorge, which is a site in East Africa that has been the source of major anthropological discoveries in the early-mid 1900’s. We also chose the name as a tribute to the scientists who made important contributions to the early studies of human origins and our African genesis

Molecular cloning of a human polypeptide related to yeast sds22, a regulator of protein phosphatase-1

Abstractsds22 is a regulatory polypeptide of protein phosphatase-1 that is required for the completion of mitosis in both fission and budding yeast. We report here the cDNA cloning of a human polypeptide that is 46% identical to yeast sds22. The human homolog of sds22 consists of 360 residues, has a calculated molecular mass of 41.6 kDa and shows a tandem array of 11 leucinerich repeat structures of 22 residues. Northern analysis revealed a major transcript of 1.39 kb in all 8 investigated human tissues. sds22 was detected by western analysis in both the cytoplasm and the nucleus of rat liver cells as a polypeptide of 44 kDa

The ethics of using transgenic non-human primates to study what makes us human

An ongoing flood of comparative genomic data is identifying human lineage specific (HLS) sequences of unknown function, and there is strong interest in investigating their functional effects. Transgenic apes, our closest evolutionary relative, have the highest potential to express HLS sequences as they are expressed in Homo sapiens and likewise experience harm from such transgenic research. These harms render the conduct of this research ethically unacceptable in apes, justifying regulatory barriers between these species and all other non-human primates for transgenic research

Finished sequence and assembly of the DUF1220-rich 1q21 region using a haploid human genome

BackgroundAlthough the reference human genome sequence was declared finished in 2003, some regions of the genome remain incomplete due to their complex architecture. One such region, 1q21.1-q21.2, is of increasing interest due to its relevance to human disease and evolution. Elucidation of the exact variants behind these associations has been hampered by the repetitive nature of the region and its incomplete assembly. This region also contains 238 of the 270 human DUF1220 protein domains, which are implicated in human brain evolution and neurodevelopment. Additionally, examinations of this protein domain have been challenging due to the incomplete 1q21 build. To address these problems, a single-haplotype hydatidiform mole BAC library (CHORI-17) was used to produce the first complete sequence of the 1q21.1-q21.2 region.ResultsWe found and addressed several inaccuracies in the GRCh37sequence of the 1q21 region on large and small scales, including genomic rearrangements and inversions, and incorrect gene copy number estimates and assemblies. The DUF1220-encoding NBPF genes required the most corrections, with 3 genes removed, 2 genes reassigned to the 1p11.2 region, 8 genes requiring assembly corrections for DUF1220 domains (~91 DUF1220 domains were misassigned), and multiple instances of nucleotide changes that reassigned the domain to a different DUF1220 subtype. These corrections resulted in an overall increase in DUF1220 copy number, yielding a haploid total of 289 copies. Approximately 20 of these new DUF1220 copies were the result of a segmental duplication from 1q21.2 to 1p11.2 that included two NBPF genes. Interestingly, this duplication may have been the catalyst for the evolutionarily important human lineage-specific chromosome 1 pericentric inversion.ConclusionsThrough the hydatidiform mole genome sequencing effort, the 1q21.1-q21.2 region is complete and misassemblies involving inter- and intra-region duplications have been resolved. The availability of this single haploid sequence path will aid in the investigation of many genetic diseases linked to 1q21, including several associated with DUF1220 copy number variations. Finally, the corrected sequence identified a recent segmental duplication that added 20 additional DUF1220 copies to the human genome, and may have facilitated the chromosome 1 pericentric inversion that is among the most notable human-specific genomic landmarks

Evolutionary and biomedical insights from the rhesus macaque genome

The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied biomedical research. We determined the genome sequence of an Indian-origin Macaca mulatta female and compared the data with chimpanzees and humans to reveal the structure of ancestral primate genomes and to identify evidence for positive selection and lineage-specific expansions and contractions of gene families. A comparison of sequences from individual animals was used to investigate their underlying genetic diversity. The complete description of the macaque genome blueprint enhances the utility of this animal model for biomedical research and improves our understanding of the basic biology of the species

Can a few non-coding mutations make a human brain?

The recent finding that the human version of a neurodevelopmental enhancer of the Wnt receptor Frizzled 8 (FZD8) gene alters neural progenitor cell cycle timing and brain size is a step forward to understanding human brain evolution. The human brain is distinctive in terms of its cognitive abilities as well as its susceptibility to neurological disease. Identifying which of the millions of genomic changes that occurred during human evolution led to these and other uniquely human traits is extremely challenging. Recent studies have demonstrated that many of the fastest evolving regions of the human genome function as gene regulatory enhancers during embryonic development and that the human-specific mutations in them might alter expression patterns. However, elucidating molecular and cellular effects of sequence or expression pattern changes is a major obstacle to discovering the genetic bases of the evolution of our species. There is much work to do before human-specific genetic and genomic changes are linked to complex human traits.Fil: Franchini, Lucia Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Pollard, Katherine S.. Gladstone Institutes; Estados Unidos. University of California; Estados Unido

Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs

The Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) mouse strains have a 16-fold difference in duration of loss of the righting response (LORR) following administration of a sedative dose of ethanol. Four quantitative trait loci (QTLs) have been mapped in these strains for this trait. Underlying each of these QTLs must be one or more genetic differences (polymorphisms in either gene coding or regulatory regions) influencing ethanol sensitivity. Because prior studies have tended to focus on differences in coding regions, genome-wide expression profiling in cerebellum was used here to identify candidate genes for regulatory region differences in these two strains. Fifteen differentially expressed genes were found that map to the QTL regions and polymorphisms were identified in the promoter regions of four of these genes by direct sequencing of ILS and ISS genomic DNA. Polymorphisms in the promoters of three of these genes, Slc22a4, Rassf2, and Tax1bp3, disrupt putative transcription factor binding sites. Slc22a4 and another candidate, Xrcc5, have human orthologs that map to genomic regions associated with human ethanol sensitivity in genetic linkage studies. These genes represent novel candidates for the LORR phenotype and provide new targets for future studies into the neuronal processes underlying ethanol sensitivity

The associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma

BACKGROUND: Maspin, a member of the serpin family, is a suppressor of tumor growth, an inhibitor of angiogenesis and an inducer of apoptosis. Maspin induces apoptosis by increasing Bax, a member of the Bcl-2 family of apoptosis-regulating proteins. In this exploratory study, we investigated the associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma (IHCCA). METHODS: Twenty-two paraffin-embedded samples were analyzed by immunohistochemical methods using Maspin, Bax and CD34 antibodies. Maspin was scored semiquantitatively (HSCORE). Apoptosis was assessed using an antibody against cleaved caspase-3. RESULTS: The strong relationship observed between the expression of Maspin and Bax, indicates that Bax is likely to be the key effector of Maspin-mediated induction of apoptosis as indicated by the activation of cleaved caspase-3. We categorized Maspin HSCORE by calculating the optimal cutpoint. A Maspin HSCORE above the cutpoint was inversely related with tumor dimension, depth of tumor and vascular invasion. Uni/multivariate analysis suggests that a Maspin HSCORE below the cutpoint significantly worsens the patients' prognosis. Tumors with Maspin HSCORE below the cutpoint had a shorter survival (11+/-5 months) than did patients with Maspin HSCORE above the cutpoint (27+/-4 months), whereas Kaplan-Meier analysis and logrank test showed no significant difference in overall survival between the patients. CONCLUSION: The associated expression of Maspin and Bax might delay tumor progression in IHCCA. Maspin above the cutpoint might counteract tumor development by increasing cell apoptosis, and by decreasing tumor mass and cell invasion. The combined expression of Maspin and Bax appears to influence the susceptibility of tumor cholangiocytes to apoptosis and thus may be involved in delaying IHCCA progression

Molecular Trajectories Leading to the Alternative Fates of Duplicate Genes

Gene duplication generates extra gene copies in which mutations can accumulate without risking the function of pre-existing genes. Such mutations modify duplicates and contribute to evolutionary novelties. However, the vast majority of duplicates appear to be short-lived and experience duplicate silencing within a few million years. Little is known about the molecular mechanisms leading to these alternative fates. Here we delineate differing molecular trajectories of a relatively recent duplication event between humans and chimpanzees by investigating molecular properties of a single duplicate: DNA sequences, gene expression and promoter activities. The inverted duplication of the Glutathione S-transferase Theta 2 (GSTT2) gene had occurred at least 7 million years ago in the common ancestor of African great apes and is preserved in chimpanzees (Pan troglodytes), whereas a deletion polymorphism is prevalent in humans. The alternative fates are associated with expression divergence between these species, and reduced expression in humans is regulated by silencing mutations that have been propagated between duplicates by gene conversion. In contrast, selective constraint preserved duplicate divergence in chimpanzees. The difference in evolutionary processes left a unique DNA footprint in which dying duplicates are significantly more similar to each other (99.4%) than preserved ones. Such molecular trajectories could provide insights for the mechanisms underlying duplicate life and death in extant genomes