The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

/pdf/initial-sequencing-and-comparative-analysis-of-the-mouse-5a9n62pifj.pdf

Initial sequencing and comparative analysis of the mouse genome.

Parkinson's disease is a common neurodegenerative disease with complex clinical features1. Autosomal recessive juvenile parkinsonism (AR-JP)2,3 maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253 (ref. 4); the former is deleted in one Japanese AR-JP patient5. By positional cloning within this microdeletion, we have now isolated a complementary DNA clone of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3–7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product ‘Parkin’.

Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

Parkinson's disease: Mechanisms and models

The distinct protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - soluble oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insoluble deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which amyloid beta-protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.

Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.

Mutations in the α-synuclein gene ( SNCA ) in the Contursi kindred ([ 1 ][1]) implicated this gene in Parkinson's disease (PD). Subsequently, α-synuclein was identified as the major component of Lewy bodies, the pathological hallmark of PD, and of glial cell cytoplasmic inclusions ([ 2 ][2]).

We

/pdf/a-synuclein-locus-triplication-causes-parkinson-s-disease-4rg8t4thvs.pdf

α-Synuclein Locus Triplication Causes Parkinson's Disease

Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

/pdf/mutation-in-the-a-synuclein-gene-identified-in-families-with-17me93ny5f.pdf

Mutation in the α-synuclein gene identified in families with Parkinson's disease

Inflammatory breast cancer is a rapidly growing, distinct form of locally advanced breast cancer that carries a guarded prognosis. To identify the genes that contribute to this aggressive phenotype, we compared under- and overexpressed sequences in an inflammatory breast tumor cell line with those of actively replicating normal human mammary epithelial cell lines using differential display. Of the 17 transcripts isolated and characterized from these experiments, overexpression of RhoC GTPase and loss of expression of a novel gene on 6q22, LIBC (lost in inflammatory breast cancer), were highly correlated ( P < 0.0095 and P < 0.0013, respectively) with the inflammatory phenotype when a panel of archival inflammatory breast cancers was compared with noninflammatory stage III breast cancers by in situ hybridization. This study suggests two new molecular markers specific for inflammatory breast cancer.

https://clincancerres.aacrjournals.org/content/clincanres/5/9/2511.full.pdf

A Novel Putative Low-Affinity Insulin-like Growth Factor-binding Protein, LIBC (Lost in Inflammatory Breast Cancer), and RhoC GTPase Correlate with the Inflammatory Breast Cancer Phenotype

We have constructed a yeast artificial chromosome contig (YAC) map of human chromosome 4q21q23 across the Parkinson's disease region by combining molecular and fluorescence in situ hybridization techniques. This map contains 55 YACs and 51 molecular markers, including 23 polymorphic markers. We have also isolated one PI and 33 bacterial artificial chromosomes located within this contig. Plasmid libraries were generated from 11 of these BAC and PI clones, and 614 random plasmid clones were sequenced for a total of about 200 kb. This contig allowed us to precisely determine the location of 18 transcripts within the D4S2460-D4S2986 interval, including the alpha-synuclein gene found to be mutated in some families with Parkinson's disease.

/pdf/contig-map-of-the-parkinson-s-disease-region-on-4q21-q23-3t04dfzucp.pdf

Contig Map of the Parkinson's Disease Region on 4q21-q23

)Center for Medical Genetics, Johns Hopkins University, 600 NorthWolfe Street, Blalock 1012G, Baltimore, MD 21287-4922, USAe-mail: imcintos@welchlink.welch.jhu.edu, Tel.: +1 410 955 7948,Fax: +1 410 614 2522H. RootGenome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USAK. M. Scott · J. E. RichardsDepartment of Ophthamology, University of Michigan Ann Arbor, MI 48105, USAM. K. McCormick

https://deepblue.lib.umich.edu/bitstream/handle/2027.42/42264/439-103-4-525_81030525.pdf;sequence=1

Holly Root

Papers

Mutation in the α-synuclein gene identified in families with Parkinson's disease

A Novel Putative Low-Affinity Insulin-like Growth Factor-binding Protein, LIBC (Lost in Inflammatory Breast Cancer), and RhoC GTPase Correlate with the Inflammatory Breast Cancer Phenotype

Contig Map of the Parkinson's Disease Region on 4q21-q23

Physical mapping of the nail patella syndrome interval at 9q34: ordering of STSs and ESTs.