Chapter 9 continued – Patterns of inheritance •The laws of Mendel

•The chromosomal basis of inheritance

•Linkage, crossing over, and mapping •Genetic diseases

•Preimplantation diagnostics

• Types of complications of the laws of Mendel

– Incomplete dominance (flower color) – Multiple alleles (ABO blood groups) – Pleiotropy (Sickle cell anemia and malaria) – Polygenic inheritance – Environment (conditional gene expression) – Linkage

Polygenic Inheritance

• Alleles have additive effects on a single characteristic

- Do not confuse with pleiotropy (single gene affects several characteristics)

Polygenic inheritance leads to continuum in the population

• Examples: Skin color and height

- The dark-skin allele for each gene (A, B, and C) contributes one “unit” of darkness to the person and is incompletely dominant to the other allele (a, b, and c)

just 3 genes can cause a near-continuum

Role of Environment • Many human characteristics result from a combination of heredity and

environment. – Height, heart disease, cancer, alcoholism, schizophrenia, asthma …

– Look at identical twins and you will see the influence of the environment

– Effects of the environment are not passed on to the next generation (recall Lamarck, Lysenko)

Both twins smoked, however, the one on the right smoked for 14 years longer, as seen by more facial wrinkles.

http://www.medicaldaily.com/how-does-smoking-cigarettes-make-your-skin-look-older-twin-study-shows-how-smoking-causes-premature

Linked Genes

• = are located on the same chromosome tend to be inherited together, i.e. do not follow Mendel’s law of independent assortment

• Gene linkage was discovered in fruit fly (Drosophila melanogaster) by Thomas Morgan

– He observed recessive mutations – Wild type: gray body (GG), long wings (LL) Mutants: black body (gg), short wings (ll)

• Do these features follow the Mendelian pattern? Test cross GgLl x ggll

?

• Mendelian pattern predicts gametes: GL, Gl, gL, gl x gl And resulting offspring: GgLl, Ggll, ggLl, ggll in equal proportions

• But the observation was: 83% of offspring maintained the parental phenotype (gray/long or black/short)

• Conclusion: Genes for body color and wing size are mostly linked (but not 100%)

Parent-like phenotypes New phenotypes

17% New phenotypes

(gray/short or black/long)

83% Parent-like phenotypes

(Gray/long or black/short)

Parental gametes

Recombinant gametes

Tetrad Crossing over

G L

g l

G L g l

G l L g

• Reason for the non-linkage in Morgan’s experiments: Crossing over in meiosis

Genetic Recombination: Crossing Over

(= new, non-parental)

• Now applying to Morgan’s experiment

– The % of recombinant offspring among total is called “recombination frequency.”

– In this case, recombinants/total x 100 = (206 + 185)/2300 x 100 = 17%

Linkage maps

• The phenomenon of crossing over can be used to map genes

– Assumption: the farther apart two genes are on a chromosome, the higher the probability of a crossover between them

– Allows to determine relative positions of genes (= linkage map)

order and distance of genes can be determined by breeding and observing the offspring

– In honor of Morgan, distances determined from recombination frequencies are given in Morgan units

• Example of a physical map (a bacterium in this case): distance is measured in kilobase pairs (1 kilobase = 1,000 nucleotides)

Physical maps

– Today, geneticists can determine the physical distances in nucleotides between linked genes (physical map) requires DNA sequencing technology

Relationship between linkage maps and physical maps

• Recombination frequencies are not uniform along the DNA sequence of a chromosome

• Different species also have different recombination frequencies

• There is no constant conversion factor from cM kb or kb cM

• 1 cM is ~ 2,000,000 base pairs in the mouse

• 1 cM is ~ 1,000,000 base pairs (1 megabase)in humans

• 1 cM is ~ 200,000 base pairs in the nematode worm

• 1 cM is ~ 3,000 base pairs in yeast

Sex Chromosomes and Sex-Linked Genes • Sex chromosomes

– Determine the sex AND influence the inheritance of certain traits that are not sexual.

Sex Determination in Humans and Fruit Flies • Sex chromosomes

– Are designated X and Y. – Determine an individual’s sex.

• In humans – Male sex is determined by a gene called

SRY (on the Y chromosome) – In the absence of SRY, ovaries instead of

testes develop – Female is the default sex: In the absence

of male determinants, a female phenotype develops

Sex-Linked Genes • Sex-linked genes

– Only some genes on sex chromosomes determine the sex

– Most genes on sex chromosomes have nothing to do with sex determination “sex-linked genes”

– X chromosome (838 protein-coding genes) has more genes than Y chromosome (53 protein-coding genes)

• Sex-linked genes were discovered in studies of fruit fly eye color

• Chromosomes

– XR : Red (wild type, dominant) – Xr : White (recessive) – Y : No eye color gene on the Y chromosome!

Xr Y XR

R r

Genotypes

Phenotypes

Females Males

• Possible combinations after breeding

• In females but not males, an Xr allele can be masked by an XR allele males are more frequently affected by the genetic disease

• Example 1: Red-green color blindness – Reason: mutation in a light receptor gene

located on X 20x more frequent in males than females

Sex-linked disorders in human

– Red-green color blindness: red → gray, green → gray, green-weak, red-weak – Human color vision depends on the differential sensitivity of three groups of

receptors in the retina, called cones (green, red, blue) – Genes for red and green receptors are located on X-chromosome, gene for blue

receptor on autosome

• Example 2: Hemophilia

– A blood-clotting disease: Excessive bleeding even after minor injuries

– Queen Victoria seems to be the first carrier

– Mutation spread through inbreeding of the “nobility” in Europe

Queen Victoria

(1819-1901)

Albert

Alice Louis

Alexandra (czarina)

Czar Nicholas II of Russia

Alexis

• Example 3: Duchenne muscular dystrophy – A progressive weakening and loss of muscle tissue (lack of a muscle protein) – Starts early wheel chair by age 12 death by age 20 – 1/3500 US American males, even more frequent in inbred communities (1/100 in

Amish community in Indiana)

Something special about the Y chromosome

• The human Y chromosome is only about one-third the size of the X chromosome.

• Most of the genes on the Y chromosomes are different from those on the X chromosome and mainly have the function to determine the male phenotype

• Human X and Y chromosomes share very little homology very little crossing over

X

Y

Fate of “red” chromosome 1st Recombination

20 generations

50 generations

Chromosomes of original population

The fate of a regular chromosome undergoing recombination (chromosomes 1, 2, …, 22, and X in females)

X

X

THE GENES ARE NOT STABLY LINKED No stable combination of alleles

The fate of a chromosome that does NOT undergo recombination (Y chromosome)

Fate of “red” chromosome No recombination

20 generations

50 generations

Chromosomes of original population Y

X

b c d E a f

THE GENES ARE STABLY LINKED Stable combination of alleles = linkage group

Sometimes (rarely), a mutation may happen on the Y chromosome. For example: d D

abcdEf abcdEf abcdEf

abcdEf

abcdEf abcdEf

abcdEf

abcDEf abcdEf abcdEf abcdEf abcdEf

abcDEf abcDEf

abcDEf abcDEf abcDEf abcDEf

abcdEf

abcdEf abcdEf Generations

b c d E a f b c D E a f

abcdEf = old linkage group abcDEf = new linkage group

The new linkage group marks all males going back to that one father

abcDEf

http://www.familytreedna.com/snps-r-us.aspx

Human migration pattern according to Y-chromosome variations Y chromosome linkage groups can be used to trace human migration in history

Can we also trace the female inheritance?

• The X chromosome does NOT have stable linkage groups cannot be used to trace female inheritance

• But mitochondria (which originated from bacteria) also contain DNA

• Mitochondria are inherited by the mother only

http://www.intechopen.com/books/gene-therapy-developments-and-future-perspectives/differential-gene-expression-and-its-possible-therapeutic-implications

Egg Sperm cells

Human Disorders Controlled by a Single Gene • Many human traits

– Show simple inheritance patterns.

Recessive Disorders

• Most human genetic disorders are recessive. – Range from relatively harmless (albinism) to deadly

– People with recessive disorders usually have normal parents (carriers)

25% of the offspring of two carriers have the disease:

• Example of a recessive disease: Cystic fibrosis

– The most common genetic disease in the USA:

– 1/2,500 whites, 1/17,000 blacks, 1/90,000 asians

– allele is carried by 1/25 whites

• Most genetic disorders are not evenly distributed across all ethnic groups

- Uneven distribution result from geographic isolation

ex) The isolated lives of Martha’s Vineyard inhabitants

• Inbreeding (mating of close relatives): endangered species such as cheetahs and pet dogs

Calculating the approximate frequency of people carrying a mutant allele Most of the carriers are heterozygous, since the disease is rare If the frequency of the carrier in the population is Y, then the probability that a

mutant sperm or egg is produced is Y/2 Then the probability that two mutant germ cells fuse is (Y/2) x (Y/2) = Y2/4 Example: 1 in 2,500 people has cystic fibrosis Y2/4 = 1/ 2,500 Y = 1/25 1 person out of 25 people carries a mutant allele, but only 1 person out of 2,500

gets the disease

Dominant Disorders

• Some dominant conditions are non-lethal (extra finger and toes, webbed fingers and toes)

• Example: Achondroplasia – Normal head and torso, short arms and legs

– 1/25,000

– Heterozygotes: have the disease

– Homozygotes: not born (= embryonic lethal)

normal individuals (> 99.99%) have two recessive alleles (homozygote recessive genotype)

A dominant allele is not necessarily more common than the corresponding recessive allele

• A key difference between dominant lethal alleles and recessive lethal alleles

– Lethal dominant alleles are rare (cannot be carried without affecting the carrier)

– Lethal recessive mutations are more common (are masked by the normal allele)

• Some dominant conditions are lethal

• Example: Huntington disease – A lethal dominant allele that escapes elimination since it does not cause death until

relatively advanced age the afflicted individuals may have babies

– Degeneration of the nervous system: uncontrolled movements, memory loss, impaired judgment, depression, loss of abilities to swallow and speak – death 10-20 years after the onset of symptoms

A dominant allele is not necessarily “better” than the corresponding recessive allele

Biology And Society: Testing Before Birth

• Should you have the fetus genetically tested?

– Parents with an increased risk of passing on a genetic defect

– Couples that include an older female

– These tests can determine genotypes or karyotypes at a stage when abortion is still possible

– Also allows to determine the sex of the unborn child

Many ethical questions result from these possibilities

Genetic testing AFTER implantation into uterus

– Chorionic villi are fingerlike extensions of the fetal part of the placenta.

– Between weeks 10 and 12 of pregnancy, not after the 13th week

– Samples are taken with a flexible tube (catheter) through the vagina/cervix or with a needle through the belly

• Chorionic villus sampling (CVS) (융모막 융모 생검법 )

– Between weeks 14 and 20 weeks of pregnancy – 10 ml of amniotic fluid (bathes the fetus) taken with needle inserted through the

abdomen – Cells from the fetus (mostly shed skin cells) are isolated and analyzed

• Amniocentesis (양수검사)

– Developmental stages of the mammalian embryo before implantation into the uterus:

1 2

3 4

5 6

7 8

Morula (8 cells)

Blastocyst

Zygote stage

2-cell stage

Compaction stage

Late morula

Early morula

(4 cells)

Best stage for pre-implantation diagnostics

Removal of one of the 8 morula cells does not kill the embryo

Genetic testing BEFORE implantation into uterus

– 1-3 cells are taken from the morula or blastocyst

– Cells are evaluated by DNA sequence analysis or specific staining

Transfer into mother

Discard Discard Discard

• Cell biopsy

• Analysis of two morula cells by chromosome-specific staining: the sex of the embryo can be determined already before implantation:

X

X

X

Y

Chr 18

Chr 18

Chr 18

Chr 18

Summary – Patterns of inheritance •Mendel discovered the gene as the smallest heritable unit underlying appearance (phenotype).

•Most phenotypes depend on many genes, and most genes can affect many phenotypes. •In populations of organisms, a given gene can come in several variants (alleles). •Eukaryotic cells typically contain 2 copies of each gene (diploidy), hence up to 2 alleles per gene.

•Morgan discovered that different genes can be physically linked (chromosomes).

•Linkage can be broken in meiosis (crossing over). This can be used for mapping chromosomes. •The Y chromosome does not undergo crossing over (almost). This can be used to trace male inheritance and human migrations in history. But female inheritance can NOT be traced by using the X chromosome (which undergoes crossing over); rather, female inheritance can be traced by following mitochondria.

• In homozygotic form, many recessive alleles can cause diseases. In heterozygotic form, many dominant alleles can cause diseases.

•Disease-causing recessive alleles are “masked” by the normal allele. •Therefore, harmful recessive alleles occur more frequently than harmful dominant alleles. •X chromosome-linked recessive alleles are not masked in males, therefore sex-linked diseases are more frequent in males.

•Modern diagnostics can identify heritable traits before birth, even before implantation

•This may raise ethical problems and some countries do not allow it.

요약- 유전의 양식

• 멘델 (Mendel)은 외관 (표현형)아래 가장 작은 유전단위로서 유전자를 발견하였다.

• 대부분의 표현형은 많은 유전자에 좌우되며, 대부분의 유전자는 많은 표현형에 영향을 줄 수 있다. • 유기체 군에서, 주어진 유전자는 몇몇의 변형 (대립형질)이 될 수 있다. • 진핵세포는 일반적으로 각 유전자 (이배체)에 대한 두 개의 복사본을 가지고 있으며, 따라서 유전자당 2개의 대립형질을 가지게 된다.

• 모건 (Morgan)은 다른 유전자들이 물리적으로 연결되어 있음을 발견하였다 (염색체).

• 연결은 감수분열 (교차)에서 파괴된다. 이는 염색체 지도에 나타낼 수 있다. • Y 염색체는 교차를 (거의) 수행하지 않는다. 이것은 남성유전과 역사상에서 인류의 이주를 추적하기 위해 사용될 수 있다. 그러나 여성유전은 X 염색체 (교차를 수행함)를 이용하여 추적할 수 없다. 대신, 여성유전은 미토콘드리아를 따라 추적될 수 있다.

• 동형 (homozygotic form)염색체에서, 많은 열성형질들은 질병을 유발할 수 있다. 이형 (heterozygotic form)에서는 많은 우성형질들이 질병을 유발할 수 있다.

• 질병을 유발하는 열성형질은 정상 대립형질에 의해 “감춰진다”. • 그러므로 해로운 열성형질은 해로운 우성형질보다 더 자주 발생한다. • X 염색체 관련 열성형질들은 남성에서는 감춰지지 않는다. 따라서 성과 관련된 질병은 남성에서 더 흔하다.

• 현대 진단법은 태어나기 전, 심지어 착상 전에도 유전 특징을 확인할 수 있다.

• 이것은 윤리적 문제를 야기하며, 몇몇 나라에서는 이를 허용하지 않는다.