Transcript 단일 유전자 대 다인자 유전

CHAPTER FOUR
Genes in pedigrees and populations
유전체 정보학 실험실
석사1년차
하홍석
4.1 Monogenic versus multifactorial inheritance
(단일 유전자 대 다인자 유전)
가장 간단한 유전 형질: 단일 좌위(locus)에
유전자형(genotype)이 있고 없음
Mendelian
OMIM
www.ncbi.nlm.nih.gov/Omim
OMIA
http://www.ncbi.nlm.nih.gov/entrez/query.
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 name을 넣는다
4.2 Mendelian pedigree patterns(멘델리안 가계 양식)
4.2.1 Dominance and recessiveness are
properties of characters, not genes
(현성과 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
4.2.2 There are five basic mendelian pedigree
patterns (5가지 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 imply
one gene - one syndrome
(한 개의 유전자-한 개의 효소는 한 개의 유전자-한 개의 증후군은 아니다.)
Locus heterogeneity
Locus heterogeneity is common in syndromes
that result from failure of a complex pathway
Allelic heterogeneity
Allelic series are a cause of clinical
heterogeneity
Cliniclal heterogeneity
4.2.5 Mitochondrial inheritance gives a
recognizable matrilinear pedigree pattern
(미토콘드리아의 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 patterns
(기본적인 가계 양식에서의 복잡화)
4.3.1 Common recessive conditions can give a
pseudo-dominant pedigree pattern
(공통 열성은 위우성 가계 양식을 나타낸다.)
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.
4.3.2 Failure of a dominant condition to manifest
is called nonpenetrance
(우성의 실패는 유전자의 비침투도라고 부른다)
(B) Autosomal dominant inheritance
with nonpenetrance in II2.
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
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
Age-related penetrance in late-onset diseases
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 ButterworthHeinemann Ltd.
4.3.3 Many conditions show variable expression
(많은 조건들은 다양한 발현을 보여준다)
(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.
◇ 증상
백색증은 유전질환의 한 종류로 백색증을 가진사람들은 눈, 피부, 머
리카락에 소량의 색소를 가지거나, 전혀 없는 것이 특징이다(어떤 경
우에는 눈에만 색소가 없는 경우도 있다). 백색증은 모든 인종에서
나타나고 대략 17,000명당 1명의 빈도로 백색증을 가지고 있는데 미
국내에서는 18,000명 정도가 백색증을 가지고 있다고 알려져 있다.
사람들의 눈은 정상적인 시력으로 발달하기 위해 멜라닌 색소가 필요
하다. 백색증을 가진 사람들은 성장기동안 정상적인 양의 멜라닌색소
를 가지고 있지 않기 때문에 시력의 손상을 입는다. 피부도 태양광으
로부터 손상을 보호하기 위해 멜라닌 색소가 필요한데 열대지역에서
백색증을 가진 많은 사람들이 피부를 보호하지 못하여 피부암에 걸리
게 된다. 주요 증상은 전신성 백색증, 안성 백색증, 부분성 백색증의
3가지 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).
4.3.4 For imprinted genes, expression depends
on parental origin(각인 유전자는 어버이 기원에 의존하는 발현을 한다)
(E) Genetic imprinting: in this family autosomal dominant BeckwithWiedemann syndrome manifests only when the gene is inherited from
the mother (family reported by Viljoen and Ramesar, 1992).
Imprinting determination of the expression
of a gene by its parental origin
4.3.5 Male lethality may complicate X-linked
pedigrees(남성의 치사는 X에 연관된 가계를 복잡하게 한다)
(F) X-linked dominant incontinentia pigmenti(색속 실조증). Affected males
abort spontaneously (small squares).
색소실조증
여아에게서 볼 수 있는 유전성 질환. 매우 특색 있는 피부증상이 차례로 번
갈아 나타난다. 먼저 제1기(炎症期)에는 보통 생후 2주 이내에 구간(軀幹)
과 사지에 홍반·팽진(膨疹)·소수포(小水疱)가 많이 생기고, 곧이어 농포·짓
무름으로 된다. 이것이 몇 주에서 몇 개월 계속되어 제2기가 된다. 각질 증
식성인 혹모양 구진(丘疹)이 많이 발생하고 부분적으로는 차례로 열을 지
어 늘어선 것도 볼 수 있다. 이 피진은 1∼2세까지 차차 없어지고 제3기(色
素沈着期)가 된다. 선모양·띠모양의 색소반이 복잡한 모양인 소용돌이모양
·그물모양으로 배열하는데, 이 증상에서 가장 특징적인 피진이다. 색소반
은 4∼5세까지 서서히 없어져가며, 이것을 제4기(消退期)라고 한다. 이 증
상은 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.
4.3.6 New mutations often complicate pedigree
interpretation, and can lead to mosaicism
(새로운 변이는 종종 가계를 해석하는 것을 어렵게하고 모자이크 현상을 가져온다)
(H) A new autosomal dominant mutation, mimicking an
autosomal or X-linked recessive pattern.
Mosaics have two (or more) genetically different cell lines
Chimeras contain cells from two separate zygotes in a single organism
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,
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 Genetics of multifactorial characters: the
polygenic threshold theory
(다인성 형질의 유전학: 다인자 유전의 역 이론)
4.4.1 Some history
continuous or quantitative characters
VS.
dichotomous characters
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
4.4.2 Polygenic theory of quantitative traits
(양적 형질의 다인자 유전의 이론)
Fig.4.11
Fig.4.12 Regression to the mean
4.4.3 Polygenic theory of discontinuous
characters(불연속 형질의 다인자유전 이론)
4.5 Factors affecting gene frequencies
(요인들은 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 between
gene frequencies and genotype frequencies(유전
자 빈도와 유전형 빈도와 의 단순한 관계가 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.
Box 4.5
Box 4.6
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 = 11/12
2pq = 2 × 1/12 × 11/12 = 22/144
q2 = 1 in 144. Thus this single-locus model predicts that 15% of females will be carriers and 0.7% will be affe
4.5.2 Genotype frequencies can be used (with
caution) to calculate mutation rates(유전자형의 빈도수는 돌
연변이율을 계산할 수 있다.)
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).
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.
4.5.3 Heterozygote advantage can be much
more important than recurrent mutation for
determining the frequency of a recessive
disease (이형접합의 이점은
잠성 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 = 0.978
p/q = 0.978 / 0.022 = 43.72 = s2/s1
If s2 = 1 (affected homozygotes never reproduce), s1 = 0.023
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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 Xinactivation (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.