Chapter 2 Transmission Genetics: Heritage from Mendel
Mendel experimental approach Background: 불연속적유전단위 (units of inheritance) 에대한확신 유전단위들의행동예측 Transmission genetics 의확립 -> 유전형질의전달방식에대한기초를제공 Advantages: many known varieties with different alternative traits, self-fertilization, easy artificial fertilization 대립관계가분명한대립형질만선택 ( 우성과열성의구별이확실하고 분리비를분명하게관찰할수있었음. 그형질의분리비를수리통계학적으로 분석 => 유전의이론을체계화 First clear exposition of the statistical rules governing the transmission of hereditary elements from generation to generation.
Mendel s Genetic Hypothesis 쌍을이루는단위요소들 (Unit factors in pairs) : 유전적특징들은각개체에쌍으로존재하는단위요소들에의해조절된다. Dominance/ Recessiveness : 한가지특징에대하여상반된인지들이한개체내에존재할때는하나의요소가다른하나에대해우성으로작용하고이때남은하나는열성이라고불린다. Segregation : 배우자형성중에쌍으로이루어진단위요소들은무작위로나누어지므로각배우자는동일한확률로한인자혹은다른인자를받게된다. (random segregation)
대립유전자 (allele) 대립인자 (allele) 한유전자좌위 (locus) 에올수있는여러유전자형태.
유전용어 True breeding( 순종 ) : 자화수분했을때대대로같은형질이나오는것 Hybrid ( 잡종 ) : 자화수분했을때우성과열성이분리되어나오는것 Dominant ( 우성 ) : 순종대립형질교배시잡종제 1 대에서나타나는형질 Recessive ( 열성 ) : 순종대립형질교배시잡종제 1 대에서나타나지않는형질 P : 어버이 F1 : 잡종제 1 세대, F2 : 잡종제 2 대 우성 : AA 순종 : AA, aa 열성 : aa 잡종 : Aa Two identical copies of the genetic information specifying the trait = homozygous ( 동형접합성 ) Different allele of the gene = heterozygous ( 이형접합성 )
Dominance & Segregation of Traits A diagrammatic explanation of the 3 : 1 ratio of dominant : recessive visible traits observed
우열의법칙 (Low of dominance) 모든생물은여러가지형질이복합적으로작용하여유전되지만 대부분대립형질간에우열관계에따라다음세대에유전되고있다. 두순계의양친을교배시켜만든 F 1 잡종에서나타나는형질을우성, 나타나지않는형질을열성이라함 형질의발현에관계하는유전자를우성유전자 ( d o m i n a n t g e n e ), 열성유전자 (recessive gene) 라함. 열성유전인자를우성유전인자가지배하기때문에발현이억제된다고생각하여지배의법칙혹은우열의법칙 (law of dominance) 라함. 한유전자좌위의두대립유전자가다르면우성대립유전자 (dominant allele) 가외형을결정하며, 열성대립유전자 (recessive allele) 는영향을미치지못함. 1 가지형질은하나의유전자의작용을받고모든우성인자는열성인자를완전히지배하것을완전우성 (complete dominance) 이라함.
Phenotype & Genotype homozygous heterozygous homozygous The genetic constitution of an organism = genotype The observable properties of an organism = phenotype
Statistical explanation of law of dominance Phenotype 질적표현형 (qualitative phenotype): e.g 완두콩모양, 색 양적표현형 (quantitaive phenotype): e.g height, 몸무게 질환에원인이되는 allele 을 A 라하고, 또다른 allele 를 a 라한다면 AA, Aa, aa => 3 가지의유전자형존재 이때, 하나의실험어떤개인이부모로부터각각하나의 allele 를전달받아하나의유전자좌 (genetic locus) 를결정하고, 그유전자형하에서병에걸리거나 (D) => 이를확률로바꿔말하면 병에걸릴확률이 1, 병에걸리지않을확률이 0 과같이표현 그러나실제로완전우성이나완전열성은드물며, 유전자형에따라병에걸릴확률이변하게된다. 이를불완전침투 (incomplete penetrance) 란한다.
질적표현형 : 각각 AA, Aa, aa 의발병확률 P(D AA)= p AA P(D Aa)= p Aa P(D aa)= p aa 양적표현형에서는양적표현형의밀도함수가정규분포를따른다고하면, 확률변수 X 의분포는 X; AA N(μ 1,σ 1 2 ) X; Aa N(μ 2,σ 2 2 ) X; aa N(μ 3,σ 3 2 ) 즉표현형의분포는유전자형에의해결정된다
Law of segregation ( 분리의법칙 ) In the formation of gametes, the paired hereditary determinants (genes) segregate in such a way that each gamete is equally likely to contain either member of the pair. 한형질에대한 2 개의대립유전자는배우자형성중에분리되어다른배우자로들어간다. Genetic cross : Aa X Aa produces A and a gametes from each parent. Punnett square shows four possible outcomes = AA, Aa, aa, and aa. Three combinations = AA, Aa, and aa produce plants with round seeds and display a round phenotype. Fourth combination = aa displays wrinkled phenotype.
Principle of Segregation 잡종제 1 대에서자가수정할떄, Y 와 y 요소는서로분리되어같은수의배우자에하나씩포함된다. 이런유전요인의분리가핵심 얻은잡종제 2 대에서우성과열성형질이일정한비 (3:1) 로분리되어나타나는것
Statistical explanation of Law of segregation 개체의유전자형을구성하는 2 개의대립형질 (allele) 은같은확률로부모로부터자식에게전달되며, 부모유래의 allele 조합이다음세대의유전자를결정한다 즉, 아버지 ( 혹은어머니 ) 로부터하나의 allele 가 1/2 의확률로다음세대에전달된다. 인간은아버지, 어머니로부터각각하나의 allele 를전달받게되므로, 아버지의유전자형이 Aa, 어머니의유전자형이 Aa 라면자식의유전자형이 AA, Aa, aa 가될확률은각각 =>
Monohybrid Genetic Cross ( 단성잡종교배 ) [ 실험방법 ] 두종류의부모계통 (P 1 ) 에서서로대조되는형태나특징을보이는개체들을교배하여첫세대 (F 1 ) 를조사한후이들첫세대를자가교배 (Selfing) 하여얻어진자손 (F 2 의 ) 형질을조사한다. [ 실험 ] 순종의 Round 완두 x 순종의 wrinkle 완두 -- (P 1 ) (AA) (aa) (F 1 ) -- 잡종의 Round 완두 x 잡종의 wrinkle 완두 (Aa) (Aa) (F 2 ) -- Round 완두 wrinkle 완두 (787 개체 ) (277 개체 )
Monohybrid Genetic Cross Parents: Aa X Aa Each parent produces A and a gametes and contributes one gamete at fertilization 1/4 AA round dominant 1/2 Aa round dominant 1/4 aa wrinkled recessive
단성잡종실험결과의특징 실험을실시한 7 쌍의대조적형질의출현이 F 2 에서약 3:1 의비율로나타났다. 부모세대의형질중첫세대에서는두형질중하나만나타나고다른형질은그다음세대에출현한다. 상반교잡 (reciprocal cross) 에영향받지않는다 성 (sex) 과관련없다. 한가지대립형질의유전패턴은한세대를건너서일정비율 (3:1) 로나타난다. Cf. Reciprocal cross ~ 상반교잡 or 상호교배 : 해당관심형질들을나타내는개체의성을바꾸어교배하는것. 예 ) 키큰완두의화분과키작은화분의난세포이용 키큰완두의난세포와키작은완두의화분이용.
Testcross analysis Testcross = a cross between an organism of dominant phenotype (genotype unknown) and an organism of recessive phenotype (genotype known to be homozygous recessive). Testcross analysis allows geneticist to determine if observed dominant phenotype is associated with a homozygous AA or heterozygous Aa genotype. Genetic cross is performed using a recessive parent = aa Testcross allows indirect determination of parental genotype
검정교배 (Test Cross): 단일형질의경우 우성표현형을나타내지만유전자형을모르는생물체를열성동형접합자와교배하여나타나는자손의표현형비로이생물체의 genotype 을알아내는방법 우성의형질을가진개체의유전자형이호모인지헤테로인지그유전자형을 알기위하여열성의어버이와교배시키는것으로검정교배결과표현형의 비가 1:1 일경우어버이는헤테로, 우성만나올경우에는호모이다??
Testcross example RR + rr = Rr => testcross produces dominant progeny only: parent homozygous Rr + rr = 1/2 Rr + 1/2 rr => testcross produces 1/2 dominant and 1/2 recessive individuals: parent heterozygous
Dihybrid Cross ( 양성잡종교배 ) Mendel studied inheritance of two different traits, such as seed color (yellow vs. green) and seed shape (round vs. wrinkled) in the same cross = dihybrid cross 동시에두가지형질을고려하는실험두인자교배 (Two factor cross) The F1 progeny were hybrid for both characteristics, and the phenotype of the seeds was round (dominant to wrinkled) and yellow (dominant to green)
멘델 : Dihybrid Cross Mendel studied inheritance of two different phenotypic traits, such as seed color (yellow vs. green) and seed shape (round vs. wrinkled) Analysis of all combinations produces 9:3:3:1 phenotypic ratio 1) round/yellow 2) round/green 3) wrinkled/yellow 4) wrinkled/green
Independent assortment ( 독립의법칙 ) Segregation of the members of any pair of alleles is independent of the segregation of other pairs in the formation of reproductive cells. 두쌍이상의대립형질이동시에유전되는경우, 각각의대립유전자는서로영향을주지않고관계없이독립적으로유전되는것
Statistical explanation of Independent assortment 분리의법칙이하나의유전자 locus 의 allele 전달에관한법칙이라면, 독립의법칙은복수의유전자좌의 allele 전달. 더욱이독립의법칙이성립하기위해서는전달에관계하는모든유전자좌가서로다른염색체에위치 2 개의유전자좌 (1) 가서로다른염색체상에있을때하나의유전자형을구성하는두개의 allele 중하나가다음세대에전달될때, 또다른유전자좌 (2) 의 allele 는유전자좌 (1) 가어떤 allele 를전달했는가에상관없이같은확률로다음세대에전달된다.
Dihybrid Testcross The progeny of testcrosses show the result of independent assortment. The double heterozygotes produce four types of gametes in equal proportions, the ww gg plants produce one type The progeny phenotypes are expected to consist of round yellow, round green, wrinkled yellow, and wrinkled green in a ratio of 1:1:1:1 This observation confirmed Mendel s assumption that the gametes of a double heterozygote included all possible genotypes in approximately equal proportions
Figure 2.14: Genotypes and phenotypes resulting from a testcross of a Ww Gg double heterozygote
Trihybrid Genetic Cross Trihybrid cross = three pairs of elements that assort independently, such as WwGgPp For any pair phenotypic ratio = 3:1 For any two pairs ratio = 9:3:3:1 Trihybrid cross pattern of segregation and independent assortment is identical to dihybrid
[ 멘델이밝힌사실 ] X X 10cm 6cm 10cm 10cm - 유전에는별도의인자가존재함. - 각형질 ( 표현형 ) 마다관여하는유전자 (genes) 는서로다름. - 각개체는각각의양친으로부터받은유전자 중하나를자손에전달한다. : 즉, 배우자 (gamete, sex cells) 는각형질 에관여하는대립유전자 (alleles) 중하나의 유전자를보유하고있다. - 부모로부터받은유전자가서로다른개체 (hetero) 에서는한쪽부모로부터받은우성 인대립유전자에의해표현형이결정됨. 10cm 10cm 6cm 6cm - 그러나다른부모로부터받은열성대립유전 자는변하지않고존재하다가해당개체가배 우자를형성할때절반의배우자에서나타남.
유전적사건의설명 : 확률의법칙 Mendelian patterns of inheritance follow laws of probability Addition Rule: The probability of the realization of one or the other of two mutually exclusive events, A or B, is the sum of their separate probabilities 사건이독립적으로동시에일어날경우 : 곱셈의법칙적용 Example) Prob {WW or Ww} = Prob {WW} + Prob{Ww} = 0.25 + 0.50 = 0.75
유전적자료에대한평가방법 멘델의 3 : 1 단성잡종 ( 분리의법칙 ) 과 9 : 3 : 3 : 1 의양성잡종 ( 독립의법칙 ) 은다음과같은가정에근거한이론적인예측이다. 1. 각대립인자들은우성이거나열성이다 2. 분리가발생한다. 3. 독립적분배가일어난다. 4. 수정은무작위적이다. 위의 2, 3, 4 의가정들은기회사건들에의해영향을받으며임의적 변동 (random fluctuation) 에종속적이고이를기회편차 (chance deviation; 우연에의한차이 ) 라고함
카이제곱 (X 2 ) 분석법검정과해석 유전학에서관찰된편차를평가할수있는가하는것은대단히중요한기술이다 자료가주어진비율, 예를들어 1 : 1, 3 : 1 혹은 9 : 3 : 3 : 1 등에맞는가를판단할때귀무가설 (null hypothesis, H 0 ) 이라는것을세움 : 측정값 ( 비율 ) 과예상값 ( 비율 ) 사이에차이가없다고가정 분명한차이는순전히기회에의한것으로간주됨 : 귀무가설이거부된다면, 관측된차이는순전히기회때문만은아니라는것 귀무가설을평가하기위해고안된가장간단한통계적시험법 : 카이제곱적합도테스트 (X 2 analysis)
가설검정 (Testing Hypotheses) 귀무가설 : null hypothesis,( H 0 ) 주어진자료가멘델의비에맞는다고 가정함. -귀무가설이채택되는경우 : 실제측정값과예상치 ( 혹은비율 ) 사이에차이가없다 - 귀무가설이기각되는경우 : 관측된분산은순전히기회때문만은아니다 ( 다른이유가존재 )
Chi-Square Analysis The test of goodness of fit( 적합성 ) = test analyzes whether observed data agree with theoretical expectation Statistically significant refers to the magnitude of the difference between the observed and the expected numbers A conventional measure of goodness of fit is a value called chi-square, c 2 c 2 = (observed expected) 2 / expected A value of c 2 = 0 means that the observed numbers fit the expected numbers perfectly
Chi-Square Analysis The critical values of P are conventionally chosen as 0.05 (the 5 percent level). To determine the P value corresponding to a calculated c 2 we need the number of degrees of freedom of the particular chi-square test The number of degrees of freedom equals the number of classes of data minus 1
유의수준과검정력 검정결과 실제현상 (True) H 0 이사실 H 1 이사실 H 0 을기각하지못함옳은결정 (TN) Type II Error (FN) H 0 을기각 Type I Error (FP) 옳은결정 (TP) 제 1 종오류 (type I error) 귀무가설이사실인데이를기각하는오류, 실제로효과가없는데효과가있다고결론을내리게되는오류 이러한오류가일어날확률의최대허용치 : 유의수준 (significance level, α) 제 2 종오류 (type II error) 귀무가설이거짓인데이를기각하지않는오류, 실제로효과가존재하는데도불구하고효과가없다고결론을내리는오류, β 검정력 (power) 귀무가설이사실이아닐때귀무가설을기각하게될확률, 1- β
유의확률 (P value) 귀무가설 H 0 하에서관측된사건이상으로귀무가설에반하는 (H 1 을지지하는 ) 사건이일어날확률 P-value 값이작을수록귀무가설에반대되는강한증거가됨 유의수준 α 귀무가설이참일때, 귀무가설을기각할확률 (Type I error) α = 0.05 또는 0.01 P-value > 유의수준 주어진유의수준하에서귀무가설을기각할만한충분한근거가없음 귀무가설을기각하지못함 (e.g 그정도면멘델비다 ) P-value < 유의수준 주어진유의수준하에서귀무가설을기각할만한충분한근거가있음 귀무가설을기각함 (e.g 차이가없다고보기힘들다 )
9:3:3:1 의검정 옥수수종실의유색 (C_) 과백색 (cc) 및딱딱한것 (W_) 과연한것 (ww) 의교잡
Graphs for interpreting goodness of fit to genetic predictions using the chi-square test
문제. 실험실에서유전학을듣는여학생이긴날개를가진정상초파리와덤피돌연변이 (Dumpy mutation) 를발현하는날개가없는초파리를교배하는실험을하였다. 그녀는이돌연변이형질이열성이라고믿고있다. F1 세대에서모든초파리들은긴날개를가지고있었다. 다음결과들은 F2에서나온형질들이다. 792 마리의긴날개초파리들 208 마리의덤피날개초파리들학생은덤피날개가열성으로유전한다는가설을세우고, F2에서나온자료들을카이제곱검정법을사용하여테스트하고자한다. a) 가정된비율은무엇인가? b) 카이제곱검정이이가설을지지하는가?
풀이 > a) 학생은 F2 자료를 (792:208) 이열성유전자들에대한멘델비인 3:1 단성잡종비에맞는다고가정하였다. b) χ 2 분석의처음단계는 3:1인지예측결과를계산하는것이다. 그다음분산 (d) 과남은숫자들을계산한다. Ratio O e d(o-e) d 2 d 2 /e ¾ 792 750 42 1764 2.35 ¼ 208 250-42 1764 7.06 total = 1000 χ 2 =Σ[(d) 2 /e] = 2.35 + 7.06 = 9.41 우리는그림 3-11 을참조하여 p 값을결정할수있다. 이값은우리가분산이기회에의한것인지 알수있게해준다. 두가지가능한결과들 (n) 이있으므로자유도 (df) 는 n-1 = 1 이다. 표는 p 가 0.01 과 0.001 사이의값임을보여준다. 그래프는약 0.001 로예측되었다. p<0.05 이므로 우리는귀무가설을기각한다. 따라서자료는 3:1 의비율에맞지않는다.
인간의유전양식 모든유전자들이멘델식으로발현되나? No! ( 멘델비의변형참고 ) 고안된교배가불가능하고, 많은수의자손을얻을수없는 경우에도유전양식을확인하는것이가능한가? Yes! (Pedigree 의이용 )
Pedigree Analysis Pedigree analysis is used to study single gene disorders, such as Huntington s Disease, a progressive neurodegenerative disorder Conventional symbols used in depicting human pedigrees
Pedigree Analysis: Dominance Dominant phenotypic traits usually appear in every generation of a pedigree. The observed pattern of inheritance occurs in dominant genetic disorders not involving the X chromosome (termed autosome) About 1/2 the offspring of an affected individual are affected The trait appears in both sexes if the gene is not on the X chromosome.
Pedigree of a human family showing the inheritance of the dominant gene for Huntington disease Huntington disease is a progressive nerve degeneration, usually beginning about middle age, that results in severe physical and mental disability and ultimately in death
Pedigree Analysis: Recessive Analysis of transmission patterns of recessive genes is used to identify carriers of recessive traits which cannot be determined by direct phenotypic analysis Two phenotypically normal (dominant) people who produce a child with a recessive genetic disorder: 1/4 probability that any of their children will be affected and 1/2 that they will be carriers The trait affects both sexes. Most affected persons have parents who are not themselves affected; the parents are heterozygous for the recessive allele and are called carriers
Albinism = absence of pigment in the skin, hair, and iris of the eyes Albinism (lack of pigmentation): ¼ the children of heterozygous parents are affected
[ 여러가지유전현상 ( 멘델법칙의특례 )] 첫번째, 우열법칙의특례 : 불완전우성, 복대립우성, 공우성등 두번째, 독립의법칙특례 : 연관과교차 세번째, 분리의법칙특례 : 억제유전자,.. 유전자의다면작용등 - 유전자간의상호작용으로이론적분리비가서로상이하게 나타나는유전현상
유전자와형질의발현관계가멘델의유전법칙과다른몇가지사실... 1. 우열의법칙은우성이열성을완전하게재배하는개념이지만 많은실험결과에서는양적형질에서는불완전한우성관계가 나타남. 2. 2 개이상의형질의경우각형질을나타나게하는유전자가 서로독립적이지만실제형질을발현하는과정중에는서로 협력하거나간섭하여다른형질을나타냄. 3. 한유전자는하나의형질에만관여하는것이아니라여러 형질의발현에관여. 4. 전혀다른좌위의유전자들에의해서동일한형질이 2 개이상 나타나는경우. - 형질의발현에는유전자들의상호간에유기적인관계가존재 - 내적, 외적환경조건도어떠한형질의발현에관여
Incomplete Dominance [ 불완전우성 ] 멘델의법칙에서는양친의한쪽형질즉우성형질만을완전하게나타내는 F 1 이존재하게되는데, 이를완전우성 (complete dominance) 이라함. Heterozygote phenotype is intermediate between dominant and recessive phenotypes. Incomplete dominance is often observed when the phenotype is quantitative rather than discrete 양친의중간적형질을가져서대립인자간의우열관계가명확하지않은 F 1 이존재 : 우성인자가열성인자를완전하게지배하지못하는중간유전현상 (intermediate inheritance) 또는불완전우성 (incomplete dominance) - 대표적인예 : Corren s 분꽃, 피부 ( 인간 ), 닭의모관, 갈색란과백색란등
Incomplete Dominance
[ 복대립유전자 (multiple alleles)] 일반적으로 1 개체 1 형질 2 개대립유전자존재 돌연변이등의요인으로 1 개체 1 형질 3 개이상의대립유전자가존재 ( 초파리의경우한 locus 에 37 개의돌연변이체가존재함 ) 하나의형질유전에 3 개또는그이상의대립유전자가관여하는유전을복대립유전자 =>presence in a population of more than two alleles of a gene Aa a1, a2, a3, a4,,,,,,,, Example) 인간의 ABO 혈액형 ABO system by three alleles-> A, B, O, AB 형
[ 공우성 (co-dominance)] 두개의유전자가우열관계가없음 두유전자가우열성에관계없이형질을독립적으로잡종 F 1 에다함께나타나게하는것 이형접합체에서양친의특성이함께나타나는경우 대표적인예 : 사람의혈액형, 누예의호랑이반점등
[ 유전자의다면작용 (pleiotropy of gene)] 하나의유전자가두개이상의형질발현을지배하는현상 - 하나의대립유전자가조직에따라다른방법으로발현됨 < 사람의경우 > 어린이눈의희자위에청색점 (blue sclera-brittle bone disease) : 칼슘대사결핍 뼈가쉽게부서짐 영아의페닐케톤뇨증 (Phenylketonurea)_ 유전병 : 페닐알라닌 (phenylalanine) 대사장애 대사산물이혈액에축적 정신박약, 머리성장저해, 흑색소결핍 ( 머리털, 피부 )
상위유전자와하위유전자 (epistatic gene and hypostatic gene) 각각의독립적인형질을발현하는두개의유전자가특정한한형질에작용할때한쪽유전자의작용이강하여 (epistasis, 상위작용 ), 다른쪽유전자의발현을억제 (hypostasis, 하위작용 ) 하는현상. (epistasis, 상위작용 ) 발현억제 (hypostasis, 하위작용 ) 형질
Expressivity and Penetrance Variation in the phenotypic expression of a particular genotype may happen because other genes modify the phenotype or because the biological processes that produce the phenotype are sensitive to environment Variable expressivity( 가변성발현율 ) refers to genes that are expressed to different degrees in different organism Penetrance( 유전률 ) refers to the proportion of organisms whose phenotype matches their genotype for a given trait. A genotype that is always expressed has a penetrance of 100 percent.
Epistasis example Epistasis refers to any type of gene interaction that results in the F2 dihybrid ratio of 9:3:3:1 being modified into some other ratio In a more general sense, it means that one gene is masking the expression of the other Purple pigment requires the dominant allele of both the C and P genes: the F2 ratio is modified to 9 purple:7 white Figure 2.24: A cross showing epistasis in the determination of flower color in peas
Summary 1. 멘델은완두에서유전양식을연구하여전달유전학의원리를확립시켰다. 2. 멘델의가정들은표현형발현의유전에대한기초를제공한다. 한쌍의대립인자인유전요소와우성열성의관계가있음을제시하였다. 3. 멘델은유전요소들이배우자형성시에나뉘어지며각배우자는동일한확률로두유전요소중하나만받게된다고가정했다. 4. 한쌍의단위요소들은다른쌍의단위요소들이분리되는것과는독립적이어서배우자들의모든가능한조합은동일한확률로형성된다. 5. 유전적비율은확률로나타내어진다. 6. 통계적분석은실험결과의타당성을검정하는데사용된다. 유전학에서는기회편차에의한예상비로부터의변화량이예측될수있다. 7. 카이제곱분석은예상값과관측값사이에실질적인차이가없다는명제 ( 영가설 ) 를평가하는데사용된다. 이것은관찰된차이가기회편차에의한것이지아닌지에대한확률을검사해준다. 8. 가계도분석은수세대를거쳐사람의형질에대한유전양식을연구하는데사용된다.