Use Of Marker Data Research Articles

On the use of marker data to determine the kinetics of the digestive behaviour of feeds

A model of the transport process that follows the progress of digesta successively through the small intestine of a monogastric is investigated. The process is multi-phase and multi-constituent, as described in detail by Bastianelli et al. [ J. Anim. Sci. , 74:1873–1887, 1996]. The model describes the movement of marker substances that are used to obtain data on the interactions between the intestinal sections and digesta with differing levels of soluble fibre. A multi-stage process is modelled by a set of coupled first order linear differential equations. Solutions of steady and initial value problems provide information on the transfer rates of the processes. Properties of the solutions as functions of system parameters are examined. References M. Renton, J. Hanan and K. Burrage, Using the canonical modelling approach to simplify the simulation of function in functional-structural plant models. New Phytologist , 166:845–857, 2005. doi:10.1111/j.1469-8137.2005.01330.x D. Bastianelli, D. Sauvant and A. Rerat, Mathematical modeling of digestion and nutrient absorption in pigs. J. Animal Science , 74:1873–1887, 1996. http://www.journalofanimalscience.org/content/74/8/1873.abstract R. G. Lentle and P. W. M. Janssen, Manipulating Digestion with Foods designed to Change the Physical Characteristics of digesta. Critical Reviews in Food Science and Nutrition , 50:130–145, 2010. doi:10.1080/10408390802248726 J. France, J. H. M. Thornley, M. S. Dhanoa and R. C. Siddons, On the mathematics of digesta flow kinetics. Journal of Theoretical Biology , 113:743–758, 1985. doi:10.1016/S0022-5193(85)80191-0 A. Mazanov and J. V. Nolan, Simulation of the dynamics of nitrogen metabolism in sheep. British Journal of Nutrition , 35:149–174, 1976. doi:10.1079/BJN19760017 A. Mazanov, Stability of Multi-pool Models with Lags. Journal of Theoretical Biology , 59:429–442, 1976. doi:10.1016/0022-5193(76)90181-8

형제 및 자매의 유전자형 자료에 기초한 전달불균형 검정법에 관한 연구

전달불균형 검정법(transmission and disequilibrium test)과 같은 가계중심(family-based) 검정법들은 질병 관련 유전자를 찾는 데 매우 유용한 방법으로 알려져 있다. 사례-대조군 연구와 달리 가계중심 검정법들은 집단혼합(population admixture)으로 인한 영향을 받지 않기 때문에 질병 관련 유전자와 표지자(marker) 사이의 집단 혼합으로 인한 가짜 연관성(spurious association)에 노출될 위험이 없다. 가계중심 검정법들은 대체로 표지자에 대한 부모의 유전자형(genotype) 정보를 필요로 한다. 그러나 고령층에서 발병하는 질병의 경우에는 발단자(proband) 부모의 유전자형을 구할 수 없는 상황에 종종 마주치게 된다. 본 논문에서는 이런 어려움을 극복하기 위해 부모의 유전자형 대신 질병에 노출되지 않은 발단자 형제나 자매의 유전자형을 이용한 검정법을 제안하고자 한다. 이를 위해 먼저 가능한 모든 일배체형(haplotype)에 대해 Mantel-Haenszel 형태의 통계량을 정의하고 그것에 기초한두 가지 검정통계량을 제안하였다. 모의실험 결과, 제안한 검정법은 집단 혼합으로부터 로버스트하고 유전 양식(mode of inheritance)에 관계 없이 상대위험(relative risk)이 증가함에 따라 단조적으로 증가하는 검정력을 갖는 것으로 나타났다. 제안한 검정법을 연세대학교 심혈관계질환 유전체연구센터로부터 수집한 자료에 적용하고 그 결과를 고찰하였다. Family-based tests such as the transmission and disequilibrium tests(TDT) have proved to be powerful tools in the search for disease genes. Unlike case-control studies, the tests are not affected by population admixture, which can lead to spurious association of multiple highly linked makers with disease-susceptible genes. Those tests have largely required knowledge of parental marker genotypes. However, parental data are often not available for late-onset diseases. In this article we propose sib-TDTs that overcome this problem by use of marker data from unaffected sib(s) instead of parents. To do this end, we fist defined a Mantel-Haenszel-type statistic for each haplotype and then proposed two tests based on this statistic. Simulation studies suggest that the proposed tests are robust to population admixture and are monotone increasing as a relative risk increases irrespective of mode of inheritance. We also illustrated the proposed tests with data adopted from Yonsei Cardiovascular Genome Center.

Improving Estimates of Genetic Maps: A Maximum Likelihood Approach

As a result of previous large, multipoint linkage studies there is a substantial amount of existing marker data. Due to the increased sample size, genetic maps estimated from these data could be more accurate than publicly available maps. However, current methods for map estimation are restricted to data sets containing pedigrees with a small number of individuals, or cannot make full use of marker data that are observed at several loci on members of large, extended pedigrees. In this article, a maximum likelihood (ML) method for map estimation that can make full use of the marker data in a large, multipoint linkage study is described. The method is applied to replicate sets of simulated marker data involving seven linked loci, and pedigree structures based on the real multipoint linkage study of Abkevich et al. (2003, American Journal of Human Genetics 73, 1271-1281). The variance of the ML estimate is accurately estimated, and tests of both simple and composite null hypotheses are performed. An efficient procedure for combining map estimates over data sets is also suggested.

Detecting Deletions in Families Affected by a Dominant Disease by Use of Marker Data

A method of testing for whether inherited deletions are a cause of a single-locus dominant disease was derived, involving analysis of the marker segregation within the pedigree of a single family that segregates for the disease. It is shown that markers can be used to test deductively for the presence of an inherited deletion. The probabilities of confirming or rejecting the presence of a deletion in an arbitrary pedigree without inbreeding are then derived. The power of the test is shown to be limited in single trios but to increase rapidly as the size of the pedigree increases. For larger pedigrees, the probabilities of confirming or rejecting a deletion are higher than 0.9 for SNPs having a minor allele frequency greater than 0.4. The probabilities are higher using multiallelic markers such as microsatellites, reaching levels as high as 0.9 in even rather small pedigrees. In certain cases the test outcome is not deductive, a deletion being neither confirmed nor rejected. It is shown to still be possible then to employ a statistical test for the presence of a deletion by use of an a priori probability for a deletion.

The genetic variance for multiple linked quantitative trait loci conditional on marker information in a crossed population

In the prediction of genetic values and quantitative trait loci (QTLs) mapping via the mixed model method incorporating marker information in animal populations, it is important to model the genetic variance for individuals with an arbitrary pedigree structure. In this study, for a crossed population originated from different genetic groups such as breeds or outbred strains, the variance of additive genetic values for multiple linked QTLs that are contained in a chromosome segment, especially the segregation variance, is investigated assuming the use of marker data. The variance for a finite number of QTLs in one chromosomal segment is first examined for the crossed population with the general pedigree. Then, applying the concept of the expectation of identity-by-descent proportion, an approximation to the mean of the conditional probabilities for the linked QTLs over all loci is obtained, and using it an expression for the variance in the case of an infinite number of linked QTLs marked by flanking markers is derived. It appears that the approach presented can be useful in the segment mapping using, and in the genetic evaluation of, crosses with general pedigrees in the population of concern. The calculation of the segregation variance through the current approach is illustrated numerically, using a small data-set.

Identification of monozygous twins and microsatellite mutation rate in pigs from QTL linkage analysis data

In previous work, microsatellite markers have primarily been tools for genome studies. However, the use of marker data can be extended beyond its original intent to maximize the amount of information obtained. There have been few studies to determine the occurrence of monozygous (MZ) twins in pigs. The advent of DNA marker technology, and microsatellites in particular, allows MZ twins to be identified based on their genotype data. To determine if MZ twin births occur in pigs, genotypes for F2 individuals, n=525, from 65 Berkshire × Yorkshire families were examined. One pair of female twins was found to have matching genotype data (95% CI: 0–2.94 twins). This is a unique result since there have been no published reports to date of twin pigs that survived until birth. Additionally, three dinucleotide microsatellite mutations were found after screening 134 565 meioses of 125 loci spanning the entire genome and the X chromosome. The average mutation rate for the population, n=570, was 2.23 × 10–5 (95% CI: 6.17 × 10–6–6.51 × 10–5). A mutation rate similar to this was published earlier for dinucleotide repeat microsatellite mutations in swine.

Use of marker haplotypes to refine covariances among relatives for breeding value estimation

Markers flanking DNA regions, where quantitative trait loci (QTL) have been previously spotted, can be used to trace the common inheritance of major genes for a better definition of covariances among animals. A practical approach to the use of marker data to refine the additive relationship matrix used in the traditional best linear unbiased prediction (BLUP) methodology is presented. The technique allows the number of the mixed model equations to be kept to an animal level, blending polygenic pedigree data with marker haplotype information. The advantage of this marker‐assisted selection (MAS) approach over BLUP selection has been assessed through a stochastic simulation. A finite locus model with 32 independent biallelic loci was generated with normally distributed allelic effects. The heritability of the trait, measured on both sexes and on females only, was set to 0.2 and 0.5. Five‐allelic markers 2, 10 and 20 cM apart, bracketed the QTL with the largest effect on the trait, accounting for 17% of the genetic variance. The bracketed QTL had two or eight alleles and its position was undefined within the bracket. Results show a moderate 2% advantage of MAS over BLUP in terms of higher genetic response when trait was recorded on both sexes and heritability was 0.2. The benefit is in the short term, but it lasts longer with polyallelic QTL. When the trait was recorded on females only, MAS produced only a small and insignificant genetic gain, but reduced the overall inbreeding in the population. MAS was also inefficient when heritability was 0.5.

Clustering of pedigrees using marker allele frequencies: impact on linkage analysis.

Ethnicity may form the basis for locus heterogeneity at certain susceptibility loci for complex diseases. Classification of pedigrees into ethnic groups is usually based upon self-report, but this may not be sensitive or specific. We investigated whether it is possible to cluster families from an admixed population using pedigree-specific marker allele frequencies. We used 323 autosomal microsatellite markers from 216 pedigrees who described themselves as either Caucasian or African American. First, we compared the stated ethnicity of pedigrees with clusters using pedigree-specific marker allele frequencies as input for a self-organizing map, a type of neural network. Using data from different chromosomes, nine pedigrees which were self-reported as African American were clustered with the Caucasian pedigrees. Removal of these nine pedigrees from the African American group did not markedly affect linkage results. We then proceeded to determine whether there was further heterogeneity between pedigrees using 1 x 3 nodes. Forty-four pedigrees were clustered in a group intermediate to the African American or Caucasian clusters. This group was composed of 36 and 8 pedigrees that described themselves as African American and Caucasian, respectively. Linkage analysis was performed in this group and results compared with the groups based upon self-reported ethnicity. Linkage to a region on chromosome 3 was observed in this intermediate group, which was more significant than any of the results obtained when pedigrees were grouped using self-reported ethnicity. Use of marker data may assist in clustering pedigrees with similar, ethnic backgrounds and may increase the power for genetic linkage studies.

A Sibship Test for Linkage in the Presence of Association: The Sib Transmission/Disequilibrium Test

Linkage analysis with genetic markers has been successful in the localization of genes for many monogenic human diseases. In studies of complex diseases, however, tests that rely on linkage disequilibrium (the simultaneous presence of linkage and association) are often more powerful than those that rely on linkage alone. This advantage is illustrated by the transmission/disequilibrium test (TDT). The TDT requires data (marker genotypes) for affected individuals and their parents; for some diseases, however, data from parents may be difficult or impossible to obtain. In this article, we describe a method, called the "sib TDT" (or "S-TDT"), that overcomes this problem by use of marker data from unaffected sibs instead of from parents, thus allowing application of the principle of the TDT to sibships without parental data. In a single collection of families, there might be some that can be analyzed only by the TDT and others that are suitable for analysis by the S-TDT. We show how all the data may be used jointly in one overall TDT-type procedure that tests for linkage in the presence of association. These extensions of the TDT will be valuable for the study of diseases of late onset, such as non-insulin-dependent diabetes, cardiovascular diseases, and other diseases associated with aging.