CpG islands (CGIs) are dense clusters of CpG sequences that punctuate the CpG-deficient human genome and associate with many gene promoters. As CGIs also differ from bulk chromosomal DNA by their frequent lack of cytosine methylation, we devised a CGI enrichment method based on nonmethylated CpG affinity chromatography. The resulting library was sequenced to define a novel human blood CGI set that includes many that are not detected by current algorithms. Approximately half of CGIs were associated with annotated gene transcription start sites, the remainder being intra- or intergenic. Using an array representing over 17,000 CGIs, we established that 6%–8% of CGIs are methylated in genomic DNA of human blood, brain, muscle, and spleen. Inter- and intragenic CGIs are preferentially susceptible to methylation. CGIs showing tissue-specific methylation were overrepresented at numerous genetic loci that are essential for development, including HOX and PAX family members. The findings enable a comprehensive analysis of the roles played by CGI methylation in normal and diseased human tissues.

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A Novel CpG Island Set Identifies Tissue-Specific Methylation at Developmental Gene Loci

''Inborn errors of metabolism,'' first recognized 100 years ago by Garrod, were seen as transforming evidence for chemical and biological individuality. Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype, was identified in 1934 by Asbjorn Folling. It is a disease with impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (HPA). Its metabolic phenotype is accountable to multifactorial origins both in nurture, where the normal nutritional experience introduces L-phenylalanine, and in nature, where mutations (4500 alleles) occur in the phenylalanine hydroxylase gene (PAH) on chromosome 12q23.2 encoding the L-phenylalanine hydroxylase enzyme (EC 1.14.16.1). The PAH enzyme converts phenylalanine to tyrosine in the presence of molecular oxygen and catalytic amounts of tetrahydrobiopterin (BH4), its nonprotein cofactor. PKU is among the first of the human genetic diseases to enter, through newborn screening, the domain of public health, and to show a treatment effect. This effect caused a paradigm shift in attitudes about genetic disease. The PKU story contains many messages, including: a framework on which to appreciate the complexity of PKU in which phenotype reflects both locus-specific and genomic components; what the human PAH gene tells us about human population genetics and evolution of modern humans; and how our interest in PKU is served by a locus-specific mutation database (http://www.pahdb.mcgill.ca; last accessed 20 March 2007). The individual Mendelian PKU phenotype has no ''simple'' or single explanation; every patient has her/his own complex PKU phenotype and will be treated accordingly. Knowledge about PKU reveals genomic components of both disease and health. Hum Mutat 28(9), 831-845, 2007. Published 2007 Wiley-Liss, Inc. y

/pdf/the-pah-gene-phenylketonuria-and-a-paradigm-shift-33z80yo58k.pdf

The PAH gene, phenylketonuria, and a paradigm shift

The centriole and basal body (CBB) structure nucleates cilia and flagella, and is an essential component of the centrosome, underlying eukaryotic microtubule-based motility, cell division and polarity. In recent years, components of the CBB-assembly machinery have been identified, but little is known about their regulation and evolution. Given the diversity of cellular contexts encountered in eukaryotes, but the remarkable conservation of CBB morphology, we asked whether general mechanistic principles could explain CBB assembly. We analysed the distribution of each component of the human CBB-assembly machinery across eukaryotes as a strategy to generate testable hypotheses. We found an evolutionarily cohesive and ancestral module, which we term UNIMOD and is defined by three components (SAS6, SAS4/CPAP and BLD10/CEP135), that correlates with the occurrence of CBBs. Unexpectedly, other players (SAK/PLK4, SPD2/CEP192 and CP110) emerged in a taxon-specific manner. We report that gene duplication plays an important role in the evolution of CBB components and show that, in the case of BLD10/CEP135, this is a source of tissue specificity in CBB and flagella biogenesis. Moreover, we observe extreme protein divergence amongst CBB components and show experimentally that there is loss of cross-species complementation among SAK/PLK4 family members, suggesting species-specific adaptations in CBB assembly. We propose that the UNIMOD theory explains the conservation of CBB architecture and that taxon- and tissue-specific molecular innovations, gained through emergence, duplication and divergence, play important roles in coordinating CBB biogenesis and function in different cellular contexts.

/pdf/stepwise-evolution-of-the-centriole-assembly-pathway-2tmu26nu73.pdf

Stepwise evolution of the centriole-assembly pathway

Substantial progress has been made in human genetics and genomics research over the past ten years since the publication of the draft sequence of the human genome in 2001. Findings emanating directly from the Human Genome Project, together with those from follow-on studies, have had an enormous impact on our understanding of the architecture and function of the human genome. Major developments have been made in cataloguing genetic variation, the International HapMap Project, and with respect to advances in genotyping technologies. These developments are vital for the emergence of genome-wide association studies in the investigation of complex diseases and traits. In parallel, the advent of high-throughput sequencing technologies has ushered in the 'personal genome sequencing' era for both normal and cancer genomes, and made possible large-scale genome sequencing studies such as the 1000 Genomes Project and the International Cancer Genome Consortium. The high-throughput sequencing and sequence-capture technologies are also providing new opportunities to study Mendelian disorders through exome sequencing and whole-genome sequencing. This paper reviews these major developments in human genetics and genomics over the past decade.

https://link.springer.com/content/pdf/10.1186%2F1479-7364-5-6-577.pdf

Human genetics and genomics a decade after the release of the draft sequence of the human genome

The GAPDH gene is highly conserved with a promoter that contains several types of regulatory elements, perhaps even in a distal intron Curiously, the transcription start site shows some ambiguity and there are codon-sharing exons at alternate exon junctions While there is only one functional gene for GAPDH in humans, the genome is littered with pseudogenes, representing a trove of researchable content Tissue-specific expression speaks to the glycolytic function of GAPDH; thus, it’s not surprising to see expression increased in cancer cells Modulation of protein levels becomes an opportunity for intervention The abundance of GAPDH in the cell provides the rationale (albeit, tenuous) for its use as a loading control The single paralogous GAPDHS, which is the spermatogenic form of the protein, provides a curious study in cell-type specificity and perhaps intervention (ie contraception) And it is no wonder that great biochemists were kept busy for decades unveiling the nuances of GAPDH enzymology While the active site of the enzyme is well-characterized and the catalytic mechanism is well-described, the role of inter-subunit interactions in catalysis still offers some mysteries, particularly with regards to other emerging enzymatic properties The GAPDH protein exhibits an intrinsic asymmetry of the subunits, which also may speak to its functional diversity

Basic Biology of GAPDH

Human chromosome 12 contains more than 1,400 coding genes and 487 loci that have been directly implicated in human disease The q arm of chromosome 12 contains one of the largest blocks of linkage disequilibrium found in the human genome Here we present the finished sequence of human chromosome 12, which has been finished to high quality and spans approximately 132 megabases, representing approximately 45% of the human genome Alignment of the human chromosome 12 sequence across vertebrates reveals the origin of individual segments in chicken, and a unique history of rearrangement through rodent and primate lineages The rate of base substitutions in recent evolutionary history shows an overall slowing in hominids compared with primates and rodents

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Yi Yuan

Papers

The finished DNA sequence of human chromosome 12