Genetic Mechanisms for Central Apneas

描述（由申请人提供）：复发性中枢性呼吸暂停的基因组方法可能提供与原发性睡眠呼吸暂停综合征和与复发性呼吸暂停和不稳定呼吸相关的神经系统疾病相关的致病性见解。该假说是小鼠1号染色体上自然发生的遗传变异是缺氧复氧后复发性呼吸暂停表型的基础。目的1是收集来自B6 x B6 a1互交小鼠对的3代谱系的约350只动物的周期性呼吸和DNA的表型数据。选择该杂交是因为1个祖父母品系（b6 a1）通过将A/J染色体1替换到B6基因组上而丧失了周期性呼吸（PB）表型。目的2将使用来自B6 x B6 a1交配方案的前100个F2后代进行低分辨率连锁扫描，以鉴定与周期性呼吸表型共分离的小鼠1号染色体的较小区域。目标3是使用B6 x B6 a1交配方案中的所有剩余动物对特定目标2中确定的区域进行高分辨率连锁扫描，以精细定位负责周期性呼吸的基因的位置。该阶段将在整个感兴趣区域中以大约20个SNP/cM的分辨率利用SNP标记。在目的4中，将来自B6和A/J小鼠品系的重组近交品系（Rl）的基因型和表型与作图结果进行比较，以确认在特定目的2和3中鉴定的作为周期性呼吸调节剂的区域，并且将使用染色体1的品系特异性单倍型信息来预测哪些其他小鼠品系可能具有周期性呼吸。识别显著影响小鼠呼吸控制差异的遗传区域将深入了解功能网络，为人类睡眠呼吸暂停的药理学现状提供信息，并为在其他医学和神经学条件下观察到的呼吸不稳定风险提供信息。

DESCRIPTION (provided by applicant): A genomic approach to recurrent central apneas might provide pathogenic insight relevant to primary sleep apnea syndromes and neurological conditions associated with recurrent apneas and unstable breathing. The hypothesis is that naturally occurring genetic variations on mouse chromosome 1 underlie a phenotype of recurrent apneas following reoxygenation from hypoxia. Aim 1 is to collect phenotype data on periodic breathing and DNA from~350 animals from 3-generational pedigrees derived from pairs of B6 x B6a1 intercross mice. This cross has been selected because 1 grandparent strain (b6a1) has lost the periodic breathing (PB) phenotype through substitution of A/J chromosome 1 onto the B6 genome. Aim 2 will be to conduct a low resolution linkage scan using the first 100 F2 offspring from the B6 x B6a1 mating scheme to identify a smaller region(s) of mouse chromosome 1 that co-segregates with the periodic breathing phenotype. Aim 3 is to perform a high resolution linkage scan on the region(s) identified in Specific Aim 2 using all remaining animals from the B6 x B6a1 mating scheme to fine map the location of the gene(s) responsible for the periodic breathing. This phase will utilize SNP markers at an approximate resolution of 20 SNPs/cM across the region(s) of interest. In Aim 4, genotypes and phenotypes from recombinant inbred strains (Rl) derived from the B6 and A/J mouse strains will be compared to the mapping results to confirm the region(s) identified in Specific Aims 2 and 3 as modulators for periodic breathing, and strain-specific haplotype information for chromosome 1 will be used to predict which other mouse strains are likely to have periodic breathing. Identification of genetic regions that contribute significantly to the variance in ventilatory control in the mouse will give insight into functional networks informative to the current poor state of pharmacology for human sleep apnea, and for the risks of breathing instability observed in other medical and neurological conditions.