Chapter 9 continued Patterns of inheritance
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1 Chapter 9 continued Patterns of inheritance The laws of Mendel The chromosomal basis of inheritance Linkage, crossing over, and mapping Genetic diseases Preimplantation diagnostics
2 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
3 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
4 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.
5 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?
6 Mendelian pattern predicts gametes: GL, Gl, gl, gl x gl And resulting offspring: GgLl, Ggll, ggll, ggll in equal proportions Parent-like phenotypes New phenotypes 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%) 83% Parent-like phenotypes (Gray/long or black/short) 17% New phenotypes (gray/short or black/long)
7 Genetic Recombination: Crossing Over Reason for the non-linkage in Morgan s experiments: Crossing over in meiosis G L g l G L Parental gametes g l Tetrad Crossing over G l g L Recombinant gametes (= new, non-parental)
8 Now applying to Morgan s experiment The % of recombinant offspring among total is called recombination frequency. In this case, recombinants/total x 100 = ( )/2300 x 100 = 17%
9 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
10 Physical maps Today, geneticists can determine the physical distances in nucleotides between linked genes (physical map) requires DNA sequencing technology Example of a physical map (a bacterium in this case): distance is measured in kilobase pairs (1 kilobase = 1,000 nucleotides)
11 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
12 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
13 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
14 Chromosomes X R : Red (wild type, dominant) X r : White (recessive) Y : No eye color gene on the Y chromosome! R r X R X r Y Possible combinations after breeding Genotypes Phenotypes Females Males In females but not males, an X r allele can be masked by an X R allele males are more frequently affected by the genetic disease
15 Sex-linked disorders in human Example 1: Red-green color blindness Reason: mutation in a light receptor gene located on X 20x more frequent in males than females 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
16 Example 2: Hemophilia Queen Victoria ( ) Albert 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 Alice Alexandra (czarina) Louis 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)
17 Something special about the Y chromosome X Y 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
18 The fate of a regular chromosome undergoing recombination (chromosomes 1, 2,, 22, and X in females) X X Chromosomes of original population 1 st Recombination Fate of red chromosome 20 generations 50 generations THE GENES ARE NOT STABLY LINKED No stable combination of alleles
19 The fate of a chromosome that does NOT undergo recombination (Y chromosome) X Y Chromosomes of original population No recombination Fate of red chromosome 20 generations 50 generations a b c d E f THE GENES ARE STABLY LINKED Stable combination of alleles = linkage group
20 Sometimes (rarely), a mutation may happen on the Y chromosome. For example: d D a b c d E f a b c D E f abcdef = old linkage group abcdef = new linkage group abcdef abcdef abcdef abcdef abcdef abcdef abcdef abcdef abcdef abcdef abcdef abcdef abcdef abcdef abcdef Generations abcdef abcdef abcdef abcdef abcdef abcdef The new linkage group marks all males going back to that one father abcdef
21 Y chromosome linkage groups can be used to trace human migration in history Human migration pattern according to Y-chromosome variations
22 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 Egg Sperm cells
23 Human Disorders Controlled by a Single Gene Many human traits Show simple inheritance patterns.
24 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:
25 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
26 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) = Y 2 /4 Example: 1 in 2,500 people has cystic fibrosis Y 2 /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
27 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
28 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 years after the onset of symptoms A dominant allele is not necessarily better 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)
29 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
30 Genetic testing AFTER implantation into uterus Chorionic villus sampling (CVS) ( 융모막융모생검법 ) 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
31 Amniocentesis ( 양수검사 ) 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
32 Genetic testing BEFORE implantation into uterus Developmental stages of the mammalian embryo before implantation into the uterus: Zygote 1 2 stage 2-cell stage Early morula (4 cells) Late morula Morula (8 cells) Compaction stage Best stage for pre-implantation diagnostics Removal of one of the 8 morula cells does not kill the embryo Blastocyst 7 8
33 1-3 cells are taken from the morula or blastocyst Cells are evaluated by DNA sequence analysis or specific staining Discard Discard Discard Transfer into mother
34 Cell biopsy Analysis of two morula cells by chromosomespecific staining: the sex of the embryo can be determined already before implantation: Chr 18 X Chr 18 X X Chr 18 Y Chr 18
35 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.
36 요약 - 유전의양식 멘델 (Mendel) 은외관 ( 표현형 ) 아래가장작은유전단위로서유전자를발견하였다. 대부분의표현형은많은유전자에좌우되며, 대부분의유전자는많은표현형에영향을줄수있다. 유기체군에서, 주어진유전자는몇몇의변형 ( 대립형질 ) 이될수있다. 진핵세포는일반적으로각유전자 ( 이배체 ) 에대한두개의복사본을가지고있으며, 따라서유전자당 2 개의대립형질을가지게된다. 모건 (Morgan) 은다른유전자들이물리적으로연결되어있음을발견하였다 ( 염색체 ). 연결은감수분열 ( 교차 ) 에서파괴된다. 이는염색체지도에나타낼수있다. Y 염색체는교차를 ( 거의 ) 수행하지않는다. 이것은남성유전과역사상에서인류의이주를추적하기위해사용될수있다. 그러나여성유전은 X 염색체 ( 교차를수행함 ) 를이용하여추적할수없다. 대신, 여성유전은미토콘드리아를따라추적될수있다. 동형 (homozygotic form) 염색체에서, 많은열성형질들은질병을유발할수있다. 이형 (heterozygotic form) 에서는많은우성형질들이질병을유발할수있다. 질병을유발하는열성형질은정상대립형질에의해 감춰진다. 그러므로해로운열성형질은해로운우성형질보다더자주발생한다. X 염색체관련열성형질들은남성에서는감춰지지않는다. 따라서성과관련된질병은남성에서더흔하다. 현대진단법은태어나기전, 심지어착상전에도유전특징을확인할수있다. 이것은윤리적문제를야기하며, 몇몇나라에서는이를허용하지않는다.
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