Preface

• 2판 나온지 8년
• entire genome 을 cover 하는 dense human marker map 이 사용가능해짐
• Mendelian trait gene 의 localization 은 거의 routine 이 되었으나, 당뇨, 어떤 종류의 암, 정신과적 질환 등의 complex trait 는 그들은 높은 유전성을 보임에도 불구하고 여전히 어려움.
• 이 책은 확률적 계산에 대한 설명은 생략, population genetics 에 대한 부분도 없음.

• This book is intended as an introduction to linkage analysis with emphasis on methodology rather than computer program.

• companion book 은 computer program 에 초점을 맞춤

• http://linkage.rockefeller.edu/ott/corr-ott.htm

• http://linkage.rockefeller.edu/ott/corr-ter.htm

• James Renwick : 첫번째로 효율적인 linkage 프로그램을 만듬. http://linkage.rockefeller.edu/ott/renwick.html

List of Symbols and Abbreviations

Introduction and Basic Genetic Principles

1.1. Linkage Analysis and the HumanGenomeProject

• Genetic linkage analysis refers to the ordering of genetic loci on a chromosome and to estimating genetic distances among them, where these distances are determined on the basis of a statistical phenomenon.

• linkage analysis 를 왜 하는가?
  • ultimate aim is to elucidate the sequence of human DNA, to understancd mechanisms of genetic disease, and, it is hoped, to prevent many of these diseases in the future.
• internet and WWW 의 impact

  • pooling results through lod scores and perhaps pooling raw data have long been a common practice in human gene mapping -> several large databases

• Although these techniques have liberated genetics from breeding experiments, many experiments can now even be carried out on computers, and this work islikely to be gaining importance in the future.

• Among all these advances in molecular genetics and computer science, linkage analysis fulfills an important role.
• Disease gene mapping is still predominantly being done by linkage analysis although many disease genes have been localized by cytogenetic techniques.

• Currently, a hot debate is on the potential merits of linkage analysis for the localization of genes underlying complex trais, that is, diseases that are clearly heritable yet do not follow any of the known modes of inheritance and are thought to be due to the interaction of multiple genes.

• In the next section, mendelian inheritance, in which a gene is viewed as a point on the genome, will be briefly described.

1.2. Mendelian Inheritance

• Until 19th century, it was common to think that genetic material did not necessarily have to be transmitted between generations but could arise spontaneously.
• [Gene] : a specific coding sequence of [DNA], the unit of transmission, recombination, and function
• exon : coding regions
• intron : intervening sequences of noncoding [DNA]

• transposons : mobile pieces of DNA. 35% of the HumanGenome is made up of transposon [DNA]

• alleles : a gene may occur in difference forms or states called alleles, each potentially having a different physical expression.

• locus : any heritable quantity that follows the mendelian laws is generally called a locus, where a gene is special type of locus, that is a locus with a function(a gene product). Well-characterized loci with a clear mendelian mode of inheritance may serve as genetic marker loci(or markers).

• gene frequencies : the relative frequencies in the population of the different alleles at a locus are called gene frequencies

• polymorphic : its most common allele has a population frequency of less than 95%(a less stringent criterion of 99% is sometimes used).
• genotype : at a given locus, the pair of alleles in an individual constitutes that individual's genotype.
• homozygous : two alleles 이 같을 때
• heterozygous
• hemizygous : X 염색체 위의 loci 일 경우, female 의 경우는 같은 용어를 사용하고, male 의 경우는 hemizygous 라 함.
• autozygous : homozygous genotype 에서 두 alleles 이 같은 조상으로부터의 alleles 의 copy 일 때 (IBD : identical by descent) 그 genotype 을 autozygous 라 함. 그렇지 않으면 allozygous.
• phenotype : the expression of a particular genotype

• penetrance : conditional probability of observing the corresponding phenotype given the specified genotype -> P(phenotype|genotype)

  • In simple case, penetrances are either 0 or 1; for many diseases, however, intermediate values of penetrances occur.
• dominant : "A" allele is expressed irrespective of the presence of an "O" allele
• recessive : "A"가 있으면 "O" 는 phenotype 에 영향을 주지 않기 때문에, 역으로 "O" 는 "A" 에 대해서 recessive.
• codominant : "A"와 "B"
• 질병 예제 : ...
• 용어의 변화 : 바람직하지는 않다?

  • mutation -> mutated allele

  • phenotype -> what you see in a disease / genotype -> what you see in a marker locus

• inconsistent or incompatible : 두개 혹은 그 이상의 genotype 이 mendelian law 따르지 않을때

• Under conditions of random mating and the absense of disturbing forces such as migration, mutation, and selection at the gene in question, a population is said to be in Hardy-Weinberg equilibrium (HWE).

• genetic drift : random force of divergence
• Although random mating implies HWE, the reverse is not necessarily true.
• haplotype : the alleles (at different genes) received by an individual from one parent are called a haplotype
• two phases of a double heterozygote
  • one phase : coupling or cis phase
  • the other phase : repulsion or trans phase
  • often, the phase of a double heterozygote is unknown
• population haplotype frequency
  • possible haplotype
  • total number of different genotypes
  • allelic association or linkage disequilibrium : 서로 다른 loci 에 있는 alleles 들이 서로 독립적으로 나타나면 haplotype 의 population frequency 는 gene frequencies 의 곱으로 표현됨.
• alleleic association or linkage disquillibrium : deviations from random occurrence of alleles in haplotypes

• For many autosomal genes, X-linked inheritance is mimicked in that the same genotype is expressed differently in males and females. This phenomenon, sex-limited inheritance must not be confused with sex-linked inheritance.

• mtDNA : maternal model of inheritance

• Gene expression not only depends on allelic status but also is determined by modification of the DNA, higher order chromosome structure, and interaction among genes. Many of these effects are due to methylation of DNA, and some are clearly heritable. A particular form of such effects is genomic imprinting.

1.3. Crossing Over and Map Distance

• 감수분열 과정에서 염색체 pair 는 4개의 strand (chromatid) 형성

• 감수분열 진행함에 따라 두개의 homologous chromosome 은 대부분의 위치에서 서로 분리되지만 하나 혹은 그 이상의 부분은 chiasmata 라고 알려진 부분에서 붙어 있다. 그들은 chromatid 사이의 crossover 의 발생을 반영한다.

• crossover point : the point on a gamete a crossover has occurred

• There always seem to occur at least one chiasma per pair of chromosome.

• crossovers occur more or less randomly along the chromosome.
• crossover frequency varies with chromosomal regions and is, for example, almost totally suppressed in chromosomal inversions.
• An exception to the randomness of occurrence of crossovers is that the likelihood for a new crossover in the immediate vicinity of an existing crossover is much smaller than expected (chiasma interference).
• Occurrence of crossover is "semirandom", which is the basis for our ability to construct genetic maps.
• These considerations suggest that the number of crossovers between two loci could serve as a stochastic measure of distance between them.
• The genetic map distance (in units of Morgans) between two loci is defined as the expected (average) number of crossovers occurring on a single chromosome (in a gamete) between the loci.
• Chiasmata 가 crossover 를 일으키고 그것은 cytogenetically observable.
• Based on higher chiasma frequencies in female than in male meioses, the female map length is approximately 1.5 times that of the male map.
• The average human chromosome is then 1.5 Morgans long; that is, it experiences an average of 1.5 crossovers.

1.4. Recombination and Genetic Linkage

• Figure 1.3, which shows three offspring affected with primary congenital glaucoma.
• We can learn two things from this example.
• This straightforward way of gene mapping is possible only under particularly favorable circumstances: no errors, known mendelian disease genotypes, and known dense marker map.
• backcross
• parental type (nonrecombinant) / nonparental type (recombinant)

• The following relation between recombination and crossing over holds: An odd number of crossover points between two loci on a gamete leads to a recombination whereas an even number of crossover points lead to a nonrecombination.

• The proportion of recombinant haplotypes (or offspring) potentially produced by a doubly heterozygous parent is called the recombination fraction, which is also the probability of occurrence of a recombination.
• With only one crossover on a chromosome, the recombination fraction between two loci at opposite ends of a chromosome is 50%.
• For loci that are in close proximity of each other, at most one crossover occurs between them so that the recombination fraction is equal to the average number of crossovers on a gamete. Thus, for small intervals, the recombination fraction directly measures genetic distance.
• The exact relation between chiasmata and recombination haplotypes is unclear; conventionally, it is assumed that one chiasma corresponds to two recombinant and two nonrecombinant haplotypes.
• genetic linkage : alleles at different gene loci appear to be genetically coupled
• genetic linkage 의 feature
  1. linkage analysis cannot be carried out with unrelated individuals but requires observations on relatives.
     • Therefore, for linkage analysis, researchers collect phenotypic information on members of family pedigrees.
     • Pedigree members fall into two classes:
       • founders : individuals whose parents are not in the pedigree
       • nonfounders : their parents are in the pedigree
  2. Recombinant and nonrecombinant haplotypes produced by a parent cannot always be distinguished.
     • A mating is potentially informative for linkage between two specific genes when at least one of the parents is a double heterozygote.
  3. For many pairs of loci, linkage analysis shows that the recombination fraction differs depending on the sex of the parent producing gamete.
• linkage group : a set of genes in which each gene is linked with at least one other gene in the same set.
• linkage group 의 숫자와 염색체쌍의 숫자가 일치하기 때문에 초기에는 linkage group 해석에 문제 없음. 지금은, linkage groups can now be interpreted as being the genetic equivalents of chromosomes on which loci are arranged in a linear order.
• X, Y 염색체의 recombination : pseudoautosomal region
• gene conversion
• As outlined above, the recombination fraction ranges from 0 for tightly linked loci to 50% for unlinked loci.

• Loci located on the same chromosome are said to be syntenic. Synteny of a pair of loci has always been shown to imply that the two loci belong to the same linkage group, althogh they are not necessarily genetically linked. The converse, that nonsyntenic loci show linkagelike associations, has occasionally been observed and has been called quasi-linkage or affinity.

• The fact that two alleles at different loci occur in the same haplotype does not imply synteni of these loci.
• The precise nature of the biochemical process of recombination is only partly understood.
• Recombination increases variability and thus accelerates evolution by natural selection, and it is involved in repairing of DNA damage.

1.5. Map Functions

• theta : probability of a recombination
• x = theta : this assumption is usually warranted for closely linked genes.

• When multiple crossovers occur between loci, recombination fractions in different intervals are no longer additivie. -> Haldane's map function

• many other map functions
• All of the above map functions except 1.1 postulate a theoretically unlimited number of crossovers.
• MAPFUN computer program
• theta 가 0.05보다 작으면 어떤 map function 도 괜찮음.
• map distance 를 recombination fraction 으로 바꿀때, map distance 의 metric 을 주의.

1.6. The Human Chromosomes

• Map distance is a genetic distnace, which need not correlate well with physical distnace.
• The only unequivocal connection between them is that genetic and physical distances are monotonic, that is, an increase in map distance translates into a larger physical distance.

• Therefore, althogh recombination fractions are poor predictors of physical distances, it is recombination fractions and not physical distance that are relevant in genetic counseling.

• The female to male map distance ratio is equal to 1.51 over the whole genome. The same ratio applies more or less to each chromosome.

1.7. Problems