連鎖分析之定批量全基因組掃描策略

A Fixed-Batch-Size Genomewide Scan Strategy in Linkage Analysis

陳淑珍(Shu-Jhen Chen)

指導教授 ： 戴政

國立臺灣大學/公共衛生學院/流行病學研究所/碩士(2005年)

https://doi.org/10.6342/NTU.2005.00673

摘要

連鎖分析（linkage analysis）已成功地運用在基因定位，尤其是人類單基因疾病所在染色體上之位置。一般可藉由等距的標識基因進行全基因組連鎖掃描。普遍的作法為判定（type）樣本中之每個個體在每個標識基因座的基因型，再進行連鎖分析。然而，這樣的作法浪費太多人力與時間在大範圍且無顯示任何連鎖證據的基因組內作基因比對。因此，連鎖分析之基因組掃描的有效設計是一個很重要的議題。
本研究提出一個定批量全基因組掃描策略，逐步選取標識基因，透過無母數分析方法之傳遞不平衡檢定（TDT），去偵測出與疾病基因相關的標識基因。最後，本研究使用電腦模擬檢驗此策略的節省效率。主要的目的是使進行基因組掃描的標識基因數能減到最少。模擬結果顯示：(1)此策略能有效節省標識基因數。(2)所需的標識基因數會隨著連鎖不平衡係數與遺傳模式而改變，但不會因疾病基因座位置不同而有所變化。本研究之定批量全基因組掃描策略在相乘性遺傳模式中的節省效率為最佳，尤其是在強連鎖不平衡之下。

關鍵字

傳遞不平衡檢定 ； 三元體 ； 單一核苷酸多型性 ； 連鎖不平衡

並列摘要

Using multiple markers to perform linkage analysis to localize genes for many monogenic human diseases has been shown successful during past years. The usual strategy is to take equally spaced markers to perform a global linkage search of the whole genome. The common approach is to type every individual in the sample at every marker locus. However, such an approach is extremely costly in labor and time because a lot of effort is wasted in genotyping large areas of the genome that do not show evidence for linkage. Developing an efficient search strategy for genome scans is therefore an important issue in linkage analysis.
In the present study, we proposed a fixed-batch-size genomewide scan strategy to select markers stepwisely to undergo linkage analysis. The transmission/disequilibrium test was used under the design of triad families. We conducted simulations to investigate the saving efficiency of the strategy. Our simulation results showed that: (1) this strategy could minimize the required number of markers in the study. (2) the required number of markers varies with the linkage disequilibrium coefficient and the mode of inheritance, but not with the disease position. The most efficient fixed-batch-size genomewide scan is for the multiplicative models, especially when the linkage disequilibrium coefficient is large.

並列關鍵字

transmission/disequilibrium test ； triad ； SNP ； linkage disequilibrium

參考文獻

Benjamini Y, and Hochberg Y. 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B 57:289-300.

Benjamini Y, and Hochberg Y. 2000. On the adaptive control of the false discovery rate in muliple testing with indendent statistics. J Educ Behav Statist 25:60-83.

Camp NJ. 1997. Genomewide transmission/disequilibrium testing consideration of the

genotypic relative risks at disease loci. Am J Hum Genet 61:1424-1430.

David ME, and Lon RC. 2004. Guidelines for genotyping in genomewide linkage studies: Single-nucleotide–polymorphism maps versus microsatellite maps. Am J Hum Genet 75:687–692.