Comparing partitions

The problem of comparing two different partitions of a finite set of objects reappears continually in the clustering literature. We begin by reviewing a well-known measure of partition correspondence often attributed to Rand (1971), discuss the issue of correcting this index for chance, and note that a recent normalization strategy developed by Morey and Agresti (1984) and adopted by others (e.g., Miligan and Cooper 1985) is based on an incorrect assumption. Then, the general problem of comparing partitions is approached indirectly by assessing the congruence of two proximity matrices using a simple cross-product measure. They are generated from corresponding partitions using various scoring rules. Special cases derivable include traditionally familiar statistics and/or ones tailored to weight certain object pairs differentially. Finally, we propose a measure based on the comparison of object triples having the advantage of a probabilistic interpretation in addition to being corrected for chance (i.e., assuming a constant value under a reasonable null hypothesis) and bounded between ±1.William H.E. Day was Acting Editor for the reviewing of this paper. We are grateful to him, Ove Frank, Charles Lewis, Glenn W. Milligan, Ivo Molenaar, Stanley S. Wasserman, and anonymous referees for helpful suggestions. Lynn Bilger and Tom Sharpe provided competent technical assistance. Partial support of Phipps Arabie's participation in this research was provided by NSF Grant SES 8310866 and ONR Contract N00014-83-K-0733.     

BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage

The breast cancer tumor-suppressor gene, BRCA1, encodes a protein with a BRCT domain-a motif that is found in many proteins that are implicated in DNA damage response and in genome stability. Phosphorylation of BRCA1 by the DNA damage-response proteins ATM, ATR and hCds1/Chk2 changes in response to DNA damage and at replication-block checkpoints. Although cells that lack BRCA1 have an abnormal response to DNA damage, the exact role of BRCA1 in this process has remained unclear. Here we show that BRCA1 is essential for activating the Chk1 kinase that regulates DNA damage-induced G2/M arrest. Thus, BRCA1 controls the expression, phosphorylation and cellular localization of Cdc25C and Cdc2/cyclin B kinase-proteins that are crucial for the G2/M transition. We show that BRCA1 regulates the expression of both Wee1 kinase, an inhibitor of Cdc2/cyclin B kinase, and the 14-3-3 family of proteins that sequesters phosphorylated Cdc25C and Cdc2/cyclin B kinase in the cytoplasm. We conclude that BRCA1 regulates key effectors that control the G2/M checkpoint and is therefore involved in regulating the onset of mitosis.     

Recommendations of the 2006 Human Variome Project meeting

Lists of variations in genomic DNA and their effects have been kept for some time and have been used in diagnostics and research. Although these lists have been carefully gathered and curated, there has been little standardization and coordination, complicating their use. Given the myriad possible variations in the estimated 24,000 genes in the human genome, it would be useful to have standard criteria for databases of variation. Incomplete collection and ascertainment of variants demonstrates a need for a universally accessible system. These and other problems led to the World Heath Organization-cosponsored meeting on June 20-23, 2006 in Melbourne, Australia, which launched the Human Variome Project. This meeting addressed all areas of human genetics relevant to collection of information on variation and its effects. Members of each of eight sessions (the clinic and phenotype, the diagnostic laboratory, the research laboratory, curation and collection, informatics, relevance to the emerging world, integration and federation and funding and sustainability) developed a number of recommendations that were then organized into a total of 96 recommendations to act as a foundation for future work worldwide. Here we summarize the background of the project, the meeting and its recommendations.     

Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema

Primary lymphoedema is a rare, autosomal dominant disorder that leads to a disabling and disfiguring swelling of the extremities and, when untreated, tends to worsen with time. Here we link primary human lymphoedema to the FLT4 locus, encoding vascular endothelial growth factor receptor-3 (VEGFR-3), in several families. All disease-associated alleles analysed had missense mutations and encoded proteins with an inactive tyrosine kinase, preventing downstream gene activation. Our study establishes that VEGFR-3 is important for normal lymphatic vascular function and that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema.     

Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion

Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.     

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.     

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.     

Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice

Imprinted genes show differential expression between maternal and paternal alleles as a consequence of epigenetic modification that can result in 'parent-of-origin' effects on phenotypic traits. There is increasing evidence from mouse and human studies that imprinted genes may influence behavior and cognitive functioning. Previous work in girls with Turner syndrome (45,XO) has suggested that there are X-linked parent-of-origin effects on brain development and cognitive functioning, although the interpretation of these data in terms of imprinted gene effects has been questioned. We used a 39,XO mouse model to examine the influence of the parental origin of the X chromosome on cognitive behaviors and expression of X-linked genes in brain. Our findings confirm the existence of X-linked imprinted effects on cognitive processes and identify a new maternally expressed imprinted gene candidate on the X chromosome, Xlr3b, which may be of importance in mediating the behavioral effects.