Human genome anatomy: BACs integrating the genetic and cytogenetic maps for bridging genome and biomedicine.

Human genome sequencing is accelerating rapidly. Multiple genome maps link this sequence to problems in biology and clinical medicine. Because each map represents a different aspect of the structure, content, and behavior of human chromosomes, these fundamental properties must be integrated with the genome to understand disease genes, cancer instability, and human evolution. Cytogenetic maps use 400-850 visible band landmarks and are the primary means for defining prenatal defects and novel cancer breakpoints, thereby providing simultaneous examination of the entire genome. Recent genetic, physical, and transcript maps use PCR-based landmarks called sequence-tagged sites (STSs). We have integrated these genome maps by anchoring the human cytogenetic to the STS-based genetic and physical maps with 1021 STS-BAC pairs at an average spacing of approximately 1 per 3 Mb. These integration points are represented by 872 unique STSs, including 642 polymorphic markers and 957 bacterial artificial chromosomes (BACs), each of which was localized on high resolution fluorescent banded chromosomes. These BACs constitute a resource that bridges map levels and provides the tools to seamlessly translate questions raised by genomic change seen at the chromosomal level into answers based at the molecular level. We show how the BACs provide molecular links for understanding human genomic duplications, meiosis, and evolution, as well as reagents for conducting genome-wide prenatal diagnosis at the molecular level and for detecting gene candidates associated with novel cancer breakpoints.

Genetic mapping of the spinocerebellar ataxia type 2 gene on human chromosome 12.

The dominant spinocerebellar ataxias are a genetically heterogeneous group of diseases leading to premature death of neurons in the cerebellum and other parts of the nervous system. The mutation causing SCA1 is on human chromosome (CHR) 6p and SCA3 is on CHR 14q. To refine the location of the SCA2 gene on CHR 12q, we performed genetic linkage analysis between the SCA2 locus and nine Ioci (D12S58, D12S78, D12S317, D12S330, D12S353, D12S84, D12S105, D12S79, and PLA2) in three SCA2 families. The highest pairwise lod scores were obtained between SCA2 and D12S84/D12S105 and D12S79. We determined the best order and genetic distances among these loci in ten multigenerational families by multipoint linkage analysis and established the following order: D12S101-D12S58/IGF1- D12S78-D12S317-D12S330/D12S353-D12S84/D 12S105-D12S79-PLA2. Using this genetic map, multipoint linkage analysis placed SCA2 between D12S84/D12S105 and D12S79.