Genes in pedigrees and populations

CHAPTER FOUR

유전체 정보학 실험실석사 1 년차

하홍석

4.1 Monogenic versus multifactorial inheritance4.1 Monogenic versus multifactorial inheritance(( 단일 유전자 대 다인자 유전단일 유전자 대 다인자 유전 ))

가장 간단한 유전 형질가장 간단한 유전 형질 : : 단일 좌위단일 좌위 (locus)(locus) 에 에 유전자형유전자형 (genotype)(genotype) 이 있고 없음이 있고 없음

MendelianMendelian

OMIMOMIMwww.ncbi.nlm.nih.gov/Omimwww.ncbi.nlm.nih.gov/Omim

OMIA OMIA http://www.ncbi.nlm.nih.gov/entrez/http://www.ncbi.nlm.nih.gov/entrez/

query.fcgi?db=omia&tool=toolbarquery.fcgi?db=omia&tool=toolbar

Genotype the genetic constitution of an individual, either overall or at a specific locus.Locus a unique chromosomal location defining the position of an individual gene or DNA sequence Mendelian of a pedigree pattern, conforming to one of the archetypic patterns shown in Figure 4.2; a character will give a mendelian pedigree pattern if it is determined at a single chromosomal location, regardless of whether or not the determinant is a gene in the molecular geneticist's sense.

Gene name 을 넣는다

4.2.1 Dominance and recessiveness are properties 4.2.1 Dominance and recessiveness are properties of characters, not genesof characters, not genes

(( 현성과 잠성은 형질의 성향이지 유전자의 성향은 아니다현성과 잠성은 형질의 성향이지 유전자의 성향은 아니다 ))

Dominant (in human genetics) describes any trait that is expressed in a heterozygote.

Recessive a character is recessive if it is manifest only in the homozygote.

Phenotype the observable characteristics of a cell or organism, including the result of any test that is not a direct test of the genotype.

Semidominant describes a mutation which, in the heterozygote, produces a phenotype intermediate (but not necessarily halfway) between the wild type and the homozygote. A term widely used in mouse genetics, but better avoided, at least in human genetics, since dominance is a property of a character and not of an allele.

Hemizygous having only one copy of a gene or DNA sequence in diploid cells. Males are hemizygous for most genes on the sex chromosomes. Deletions occurring on one autosome produce hemizygosity in males and in females

4.2 Mendelian pedigree patterns4.2 Mendelian pedigree patterns(( 멘델리안 가계 양식멘델리안 가계 양식 ))

4.2.2 There are five basic mendelian pedigree patt4.2.2 There are five basic mendelian pedigree patterns erns (5(5 가지 기본적인 멘델리안 가계 양식이 있다가지 기본적인 멘델리안 가계 양식이 있다 ))

Figure 4.1. Main symbols used in pedigrees. Generations are usually labeled in Roman numerals, and individuals within each generation in Arabic numerals; III-7 or III7 is the seventh person from the left (unless explicitly numbered otherwise) in generation III. An arrow can be used to indicate the proband or propositus 발단자 (female: proposita) through whom the family was ascertained

Figure 4.2. Basic mendelian pedigree patterns. (A) Autosomal dominant; (B) autosomal recessive; (C) X-linked recessive; (D) X-linked dominant; (E) Y-linked. The risk for the individuals marked with a query are (A) 1 in 2, (B) 1 in 4, (C) 1 in 2 males or 1 in 4 of all offspring, (D) negligibly low for males, 100% for females. See Section 4.2 and Figure 4.5 for complications to these basic patterns.

4.2.4 One gene - one enzyme does not 4.2.4 One gene - one enzyme does not imply one gene - one syndromeimply one gene - one syndrome(( 한 개의 유전자한 개의 유전자 -- 한 개의 효소는 한 개의 유전자한 개의 효소는 한 개의 유전자 -- 한 개의 증후군은 아니다한 개의 증후군은 아니다 .).)

Locus heterogeneity Locus heterogeneity Locus heterogeneity is common in syndromes that rLocus heterogeneity is common in syndromes that r

esult from failure of a complex pathwayesult from failure of a complex pathway

Allelic heterogeneityAllelic heterogeneityAllelic series are a cause of clinical heterogeneityAllelic series are a cause of clinical heterogeneity

Cliniclal heterogeneityCliniclal heterogeneity

4.2.5 Mitochondrial inheritance gives a recognizable 4.2.5 Mitochondrial inheritance gives a recognizable matrilinear pedigree patternmatrilinear pedigree pattern

(( 미토콘드리아의 유전은 모계 유전의 가계양식을 보여준다미토콘드리아의 유전은 모계 유전의 가계양식을 보여준다 ))

Figure 3.4. Pedigrees of mitochondrial diseases. A typical pedigree pattern, showing mitochondrially-determined hearing loss (family reported by Prezant et al., 1993).

http://www.mitomap.org

4.3 Complications to the basic pedigree 4.3 Complications to the basic pedigree patterns patterns (( 기본적인 가계 양식에서의 복잡화기본적인 가계 양식에서의 복잡화 ))

Figure 4.5. Complications to the basic mendelian patterns. (A) A common recessive, such as blood group O, can give the appearance of a dominant pattern.

4.3.1 Common recessive conditions can 4.3.1 Common recessive conditions can give a pseudo-dominant pedigree give a pseudo-dominant pedigree

patternpattern(( 공통 열성은 위우성 가계 양식을 나타낸다공통 열성은 위우성 가계 양식을 나타낸다 .).)

4.3.2 Failure of a dominant condition to manifest is 4.3.2 Failure of a dominant condition to manifest is called called nonpenetrancenonpenetrance

(( 우성의 실패는 유전자의 비침투도라고 부른다우성의 실패는 유전자의 비침투도라고 부른다 ) )

Nonpenetrance the situation when somebody carrying an allele that normally causes a dominant phenotype does not show that phenotype. Due to the effect of other genetic loci or of the environment. A pitfall in genetic counseling. Penetrance the frequency with which a genotype manifests itself in a given phenotype (B) Autosomal dominant inheritance wit

h nonpenetrance in II2.

Figure 4.6 The spectrum of human characters. Few characters are purely mendelian, purely polygenic or purely environmental. Most depend on some mix of major and minor genetic determinants, together with environmental influences. The mix of factors determining any given character could be represented by a point located somewhere within the triangle

Figure 4.7 Age of onset curve for Huntington disease. Curve A: probability that an individual carrying the disease gene will have developed symptoms by a given age. Curve B: risk that a healthy child of an affected parent carries the disease gene at a given age. Reproduced from Harper (1998)Genetic Counselling, 5th edn, with permission from Butterworth-Heinemann Ltd.

Age-related penetrance in late-onset diseases

(C) Autosomal dominant inheritance with variable expression: in this family with Waardenburg syndrome, shading of 1st quadrant = hearing loss; 2nd quadrant = different colored eyes; 3rd quadrant = white forelock; 4th quadrant = premature graying of hair.

Variable expression Variable extent and intensity of phenotypic signs among people with a given genotype.

4.3.3 Many conditions show variable 4.3.3 Many conditions show variable expression expression

(( 많은 조건들은 다양한 발현을 보여준다많은 조건들은 다양한 발현을 보여준다 ))

◇ 증상 백색증은 유전질환의 한 종류로 백색증을 가진사람들은 눈 , 피부 , 머리카락에 소량의 색소를 가지거나 , 전혀 없는 것이 특징이다 ( 어떤 경우에는 눈에만 색소가 없는 경우도 있다 ). 백색증은 모든 인종에서 나타나고 대략 17,000 명당 1 명의 빈도로 백색증을 가지고 있는데 미국내에서는 18,000 명 정도가 백색증을 가지고 있다고 알려져 있다 . 사람들의 눈은 정상적인 시력으로 발달하기 위해 멜라닌 색소가 필요하다 . 백색증을 가진 사람들은 성장기동안 정상적인 양의 멜라닌색소를 가지고 있지 않기 때문에 시력의 손상을 입는다 . 피부도 태양광으로부터 손상을 보호하기 위해 멜라닌 색소가 필요한데 열대지역에서 백색증을 가진 많은 사람들이 피부를 보호하지 못하여 피부암에 걸리게 된다 . 주요 증상은 전신성 백색증 , 안성 백색증 , 부분성 백색증의 3 가지 타입이 있다 .

(D) Genetic imprinting: in this family autosomal dominant glomus tumors manifest only when the gene is inherited from the father (family reported by Heutink et al., 1992).

(E) Genetic imprinting: in this family autosomal dominant Beckwith-Wiedemann syndrome manifests only when the gene is inherited from the mother (family reported by Viljoen and Ramesar, 1992).

4.3.4 For imprinted genes, expression 4.3.4 For imprinted genes, expression depends on parental origindepends on parental origin(( 각인 유전자는 어버이 기원에 각인 유전자는 어버이 기원에

의존하는 발현을 한다의존하는 발현을 한다 ) )

Imprinting determination of the expression of a gene by its parental origin

(F) X-linked dominant incontinentia pigmenti( 색속 실조증 ). Affected males abort spontaneously (small squares).

4.3.5 Male lethality may complicate X-4.3.5 Male lethality may complicate X-linked pedigreeslinked pedigrees(( 남성의 치사는 남성의 치사는 XX 에 연관된 가계를 복잡하게 한다에 연관된 가계를 복잡하게 한다 ))

색소실조증

여아에게서 볼 수 있는 유전성 질환 . 매우 특색 있는 피부증상이 차례로 번갈아 나타난다 . 먼저 제 1 기 ( 炎症期 ) 에는 보통 생후 2 주 이내에 구간( 軀幹 ) 과 사지에 홍반 · 팽진 ( 膨疹 )· 소수포 ( 小水疱 ) 가 많이 생기고 , 곧이어 농포 · 짓무름으로 된다 . 이것이 몇 주에서 몇 개월 계속되어 제 2기가 된다 . 각질 증식성인 혹모양 구진 (丘疹 ) 이 많이 발생하고 부분적으로는 차례로 열을 지어 늘어선 것도 볼 수 있다 . 이 피진은 1∼2세까지 차차 없어지고 제 3 기 (色素沈着期 ) 가 된다 . 선모양 ·띠모양의 색소반이 복잡한 모양인 소용돌이모양 ·그물모양으로 배열하는데 , 이 증상에서 가장 특징적인 피진이다 . 색소반은 4∼5세까지 서서히 없어져가며 , 이것을 제 4 기 (消退期 ) 라고 한다 . 이 증상은 우성유전이며 , 소인 (素因 ) 을 가진 임산부의 태아 중 남아는 사산되고 여아는 환자( 반수가 나타난다 ) 가 된다 . 생명의 예후는 양호하며 피진도 몇 년이면 없어지나 , 약 반수에 다른 기형이 합병되어 탈모반 , 치아이상 , 사시 등의 안과적 이상 , 간질 등의 중추신경이상이 나타난다

(G) An X-linked recessive pedigree where inbreeding gives an affected female and apparent male-to-male transmission.

(H) A new autosomal dominant mutation, mimicking an autosomal or X-linked recessive pattern.

4.3.6 New mutations often complicate pedigree interpretat4.3.6 New mutations often complicate pedigree interpretation, and can lead to mosaicismion, and can lead to mosaicism

((새로운 변이는 종종 가계를 해석하는 것을 어렵게하고 모자이크 현상을 가져온다새로운 변이는 종종 가계를 해석하는 것을 어렵게하고 모자이크 현상을 가져온다 ))

Mosaic an individual who has two or more genetically different cell lines derived from a single zygote. The differences may be point mutations, chromosomal changes,

Mosaics have two (or more) genetically different cell linesMosaics have two (or more) genetically different cell lines

Chimeras contain cells from two separate zygotes in a single organism

Figure 4.10. Mosaics and chimeras. Mosaics have two or more genetically different cell lines derived from a single zygote. The genetic change indicated may be a gene mutation, a numerical or structural chromosomal change, or in the special case of lyonization, X-inactivation. A chimera is derived from two zygotes, which are usually both normal but genetically distinct.

4.4.1 Some history4.4.1 Some history

Dichotomous character a character like polydactyly, which some people have and others do not have as opposed to a continuous character like height, which everybody has, but to differing degree Polygenic character a character determined by the combined action of a number of genetic loci. Mathematical polygenic theory

continuous or quantitative characters

dichotomous characters

VS.

4.4 Genetics of multifactorial characters: the polyg4.4 Genetics of multifactorial characters: the polygenic threshold theoryenic threshold theory

(( 다인성 형질의 유전학다인성 형질의 유전학 : : 다인자 유전의 역 이론다인자 유전의 역 이론 ))

4.4.2 Polygenic theory of quantitative traits4.4.2 Polygenic theory of quantitative traits(( 양적 형질의 다인자 유전의 이론양적 형질의 다인자 유전의 이론 ))

Fig.4.11

Fig.4.12 Regression to the mean

4.4.3 Polygenic theory of discontinuous characters4.4.3 Polygenic theory of discontinuous characters((불연속 형질의 다인자유전 이론불연속 형질의 다인자유전 이론 ))

4.5 Factors affecting gene frequencies 4.5 Factors affecting gene frequencies (( 요인들은 유전자 빈도에 영향을 끼친다요인들은 유전자 빈도에 영향을 끼친다 ))

1. 한 유전적 집단에 속하는 개체 수가 무한히 많아야한다 .

2. 짝짓기가 무작위적 (random) 으로 이뤄져야 한다 .

3. 자연선택이 없어야 한다 .

4. 돌연변이가 없어야 한다 .

5. 유전자 흐름 (gene flow) 이 없어야 한다 .

4.5.1 There can be a simple relation 4.5.1 There can be a simple relation between gene frequencies and between gene frequencies and

genotype frequenciesgenotype frequencies(( 유전자 빈도와 유전형 빈도와 의 단순한 유전자 빈도와 유전형 빈도와 의 단순한 관계가 있을 수 있다관계가 있을 수 있다 ))

-Pick an allele at random from the gene pool. There is a chance p that it is A1 and a chance q that it is A2.

- Pick a second allele at random. Again the chance of picking A1 is p and the chance of picking A2 is q (we assume the gene pool is sufficiently large that removing the first allele has not significantly changed the gene frequencies of the remaining alleles). * The chance that both alleles were A1 is p2. * The chance that both alleles were A2 is q2. * The chance that the first allele was A1 and the second A2 is pq. the chance that the first was A2 and the second A1 is qp. overall, the chance of picking one A1 and one A2 allele is 2pq.

An autosomal recessive condition affects 1 newborn in 10 000. What is the expected frequency of carriers?q2 is 10-4, and therefore q = 10-2 or 1/100.1 in 100 genes at the A locus are a, 99/100 are A.The carrier frequency, 2pq, is 2 × 99/100 × 1/100, very nearly 1 in 50.If a parent of a child affected by the above condition remarries, what is the risk of producing an affected child in the new marriage?To produce an affected child, both parents must be carriers, and the risk is then 1 in 4.

Thus the overall risk is:

This assumes there is no family history of the same disease in the new spouse's family.X-linked red-green color blindness affects 1 in 12 British males; what proportion of females will be carriers and what proportion will be affected?q = 1/12, therefore p = 11/122pq = 2 × 1/12 × 11/12 = 22/144q2 = 1 in 144. Thus this single-locus model predicts that 15% of females will be carriers and 0.7% will be affe

Box 4.6

Box 4.5

4.5.2 Genotype frequencies can be used (with caut4.5.2 Genotype frequencies can be used (with caution) to calculate mutation ratesion) to calculate mutation rates(( 유전자형의 빈도수는 유전자형의 빈도수는

돌연변이율을 계산할 수 있다돌연변이율을 계산할 수 있다 .).)

For an autosomal recessive condition, a proportion q2 of the population are affected. The loss of disease genes each generation is sq2. This is balanced by mutation at the rate of m(1 - q2) where m is the mutation rate per gene per generation. At equilibrium sq2 = m(1 - q2), or approximately (if q is small) m = sq2.

For a rare autosomal dominant condition homozygotes are excessively rare. Heterozygotes occur with frequency 2pq (frequency of disease gene = p). Only half the genes lost through their reproductive failure are the disease allele, so the rate of gene loss is very nearly sp. Again this is balanced by a rate of new mutation of mq2, which is approximately m if q is almost 1. Thus m= sp.

For an X-linked recessive disease the rate of gene loss through affected males is sq. This is balanced by a mutation rate 3m, since all X chromosomes in the population are available for mutation, but only the one third of X chromosomes which are in males are exposed to selection. Thus m = sq/3.

coefficient of selection (s) the relative chance of reproductive failure of a genotype due to selection (the fittest type in the population has s = 0, a genetic lethal has s = 1).

4.5.3 Heterozygote advantage can be much more i4.5.3 Heterozygote advantage can be much more important than recurrent mutation for determining thmportant than recurrent mutation for determining th

e frequency of a recessive disease e frequency of a recessive disease (( 이형접합의 이점은 이형접합의 이점은 잠성 질환의 빈도를 결정함에 있어서의 빈발하는 돌연변이 보다 더 중요할 것이다잠성 질환의 빈도를 결정함에 있어서의 빈발하는 돌연변이 보다 더 중요할 것이다 ))

Box 4.8: Selection in favor of heterozygotes for cystic fibrosis

For CF, the disease frequency in the UK is about one in 2000 births.q2 is 5 × 10-4, therefore q = 0.022 and p = 1 - q = 0.978p/q = 0.978 / 0.022 = 43.72 = s2/s1If s2 = 1 (affected homozygotes never reproduce), s1 = 0.023

ReferencesReferences

D.H. Cohn, B.J. Starman, B. Blumberg, and P.H. Byers. (1990). Recurrence of lethal osteogenesis imperfecta due to parental mosaicism fD.H. Cohn, B.J. Starman, B. Blumberg, and P.H. Byers. (1990). Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a dominant mutation in a human type I collagen gene (or a dominant mutation in a human type I collagen gene (COL1A1COL1A1) ) Am. J. Hum. Genet.Am. J. Hum. Genet. 46: 591-601. 46: 591-601. ((PubMedPubMed))

R.A. Fisher. (1918). The correlation between relatives under the supposition of mendelian inheritance R.A. Fisher. (1918). The correlation between relatives under the supposition of mendelian inheritance Trans. Roy. Soc.Trans. Roy. Soc. 52: 399-433. 52: 399-433.

Harper PS (1998) Harper PS (1998) Genetic Counselling,Genetic Counselling, 5th edn. Butterworth-Heinemann, Oxford. 5th edn. Butterworth-Heinemann, Oxford.

P. Heutink, A.G. van der Mey, and L.A. Sandkujl. (1992). A gene subject to genomic imprinting and responsible for hereditary paragangliomP. Heutink, A.G. van der Mey, and L.A. Sandkujl. (1992). A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to chromosome 11q23 qter as maps to chromosome 11q23 qter Hum. Mol. Genet.Hum. Mol. Genet. 1: 7-10. 1: 7-10. ((PubMedPubMed))

G.B. Pier, M. Grout, and T. Zaidi. (1998). G.B. Pier, M. Grout, and T. Zaidi. (1998). Salmonella typhiSalmonella typhi uses CFTR to enter intestinal epithelial cells uses CFTR to enter intestinal epithelial cells NatureNature 393: 79-82. 393: 79-82. ((PubMedPubMed))

T.R. Prezant, J.V. Agapian, and M.C. Bowman. (1993). Mitochondrial ribosomal RNA mutation associated with both antibiotic induced and T.R. Prezant, J.V. Agapian, and M.C. Bowman. (1993). Mitochondrial ribosomal RNA mutation associated with both antibiotic induced and non syndromic deafness non syndromic deafness Nature Genet.Nature Genet. 4: 289-294. 4: 289-294. ((PubMedPubMed))

P. Riordan-Eva and A.E. Harding. (1995). Leber's hereditary optic atrophy: the clinical relevance of different mitochondrial DNA mutations P. Riordan-Eva and A.E. Harding. (1995). Leber's hereditary optic atrophy: the clinical relevance of different mitochondrial DNA mutations J. Med. Genet,.J. Med. Genet,. 32: 81-87. 32: 81-87. ((PubMedPubMed))

R.J.H. Smith, C.I. Berlin, and J.F. Hejtmancik. (1994). Clinical diagnosis of the Usher syndromes R.J.H. Smith, C.I. Berlin, and J.F. Hejtmancik. (1994). Clinical diagnosis of the Usher syndromes Am. J. Med. Genet.Am. J. Med. Genet. 50: 32-38. 50: 32-38. ((PubMedPubMed))

L. Strain, J.C. Dean, M.P. Hamilton, and D.T. Bonthron. (1998). A true hermaphrodite chimera resulting from embryo amalgamation after iL. Strain, J.C. Dean, M.P. Hamilton, and D.T. Bonthron. (1998). A true hermaphrodite chimera resulting from embryo amalgamation after in vitro fertilization n vitro fertilization N. Engl. J. Med.N. Engl. J. Med. 338: 166-169. 338: 166-169. ((PubMedPubMed))

M.G. Sweeney, M.B. Davis, A. Lashwood, M. Brockington, A. Toscano, and A.E. Harding. (1992). Evidence against an X-linked locus close tM.G. Sweeney, M.B. Davis, A. Lashwood, M. Brockington, A. Toscano, and A.E. Harding. (1992). Evidence against an X-linked locus close to DXS7 determining visual loss susceptibility in British and Italian families with Leber hereditary optic neuropathy o DXS7 determining visual loss susceptibility in British and Italian families with Leber hereditary optic neuropathy Am. J. Hum. Genet.Am. J. Hum. Genet. 51: 51: 741-748. 741-748. ((PubMedPubMed))

M.A. Van der Meulen, M.J.P. van der Meulen, and G.J. te Meerman. (1995). Recurrence risk for germinal mosaics revisited M.A. Van der Meulen, M.J.P. van der Meulen, and G.J. te Meerman. (1995). Recurrence risk for germinal mosaics revisited J. Med. Genet.J. Med. Genet. 32: 102-104. 32: 102-104. ((PubMedPubMed))

D. Viljoen and R. Ramesar. (1992). Evidence for paternal imprinting in familial Beckwith-Wiedemann syndrome D. Viljoen and R. Ramesar. (1992). Evidence for paternal imprinting in familial Beckwith-Wiedemann syndrome J. Med. Genet.J. Med. Genet. 29: 221-22 29: 221-225. 5. ((PubMedPubMed))

D.C. Wallace. (1994). Mitochondrial DNA sequence variation in human evolution and disease D.C. Wallace. (1994). Mitochondrial DNA sequence variation in human evolution and disease Proc. Natl Acad. Sci. USAProc. Natl Acad. Sci. USA 91: 8739-8746. 91: 8739-8746. ((PubMedPubMed)) (Full Text in PMC)(Full Text in PMC)

A.O.M. Wilkie. (1994). The molecular basis of dominance A.O.M. Wilkie. (1994). The molecular basis of dominance J. Med. Genet.J. Med. Genet. 31: 89-98. 31: 89-98. ((PubMedPubMed))

Autosomal dominant inheritance (Figure 4.2A)

An affected person usually has at least one affected parent (for exceptions see Figure 4.4). Affects either sex. Transmitted by either sex. A child of an affected × unaffected mating has a 50% chance of being affected (this assumes the affected parent is heterozygous, which is usually true for rare conditions).

Autosomal recessive inheritance (Figure 4.2B)

Affected people are usually born to unaffected parents. Parents of affected people are usually asymptomatic carriers. There is an increased incidence of parental consanguinity. Affects either sex. After the birth of an affected child, each subsequent child has a 25% chance of being affected.

X-linked recessive inheritance (Figure 4.2C)

Affects mainly males. Affected males are usually born to unaffected parents; the mother is normally an asymptomatic carrier and may have affected male relatives. Females may be affected if the father is affected and the mother is a carrier, or occasionally as a result of non-random X-inactivation (Section 4.2.2). There is no male-to-male transmission in the pedigree (but matings of an affected male and carrier female can give the appearance of male to male transmission, see Figure 4.5G).

X-linked dominant inheritance (Figure 4.2D)

Affects either sex, but more females than males. Females are often more mildly and more variably affected than males. The child of an affected female, regardless of its sex, has a 50% chance of being affected. For an affected male, all his daughters but none of his sons are affected.

Y-linked inheritance (Figure 4.2E)

Affects only males. Affected males always have an affected father (unless there is a new mutation). All sons of an affected man are affected.