Human Genetics Phenotype: observed physical and functional traits Genotype: complete set of genes and alleles Alleles: Different versions of homologous genes ex. B and b Note definitions. Phenotype is result of proteins made by our cells. Includes appearance and behavior, in some cases. Phenotype can be result of quantitative differences, I.e., amount of particular proteins, not just presence or absence. Genotype is entire set of DNA per cell; half from each parent. All genes, all versions of those genes (alleles) Relationship btw alleles can be dominant /recessive as shown here by B/b or other, TBDiscussed.

Human genetics How are gametes made? How does chromosome behavior affect inheritance of traits? What are your questions regarding human genetics? how do traits skip generations? Why do males inherit certain traits more often than females? Why are children NOT carbon copies of their parents? How can a pedigree chart of family members help determine the best treatment for my health? How do parent s determine genetic risks of any children?

Somatic cells are diploid. Gametes are haploid, with only one set of chromosomes Genome = one complete set of chromosomes for an organism. So, humans have 23 xsomes per genome. Each cell has two sets, th4 diploid. Karyotype shows all 23 pairs, organized by size and centromere position. Homologous xsomes contain genes for same trait, but can have different version of each gene (different alleles). Sex xsomes, X and Y, have different structure, do not contain same genes. Y is missing most of one arm. Determines gender, XX = female, XY = male. Sperm are gametes with only one set of xsomes, I.e., 23 xsomes, one of each homologue. Egg is also haploid. Necessary to maintain same number of xsomes for each generation.

a SPERMATOGENESIS b OOGENESIS spermatogonium oogonium primary spermatocyte primary oocyte meiosis l secondary spermatocyte secondary oocyte Sperm and egg formation in humans. Meisosis divides xsomes such that each gamete is haploid, has only one genome. Not just any 23 xsomes, but one xsome of each homologous pair. Requires two cell divisions. Note differences btw meiosis and mitosis. (ch 17) In sperm formation (spermatogenesis), diploid cells called spermatogonia produce primary spermatocytes. The primary spermatocytes are the diploid cells that go through meiosis, yielding haploid secondary spermatocytes. These spermatocytes then go through meiosis II, yielding four haploid spermatids that will develop into mature sperm cells. In egg formation (oogenesis), cells called oogonia, produced before the birth of the female, develop into primary oocytes. These diploid cells will remain in meiosis I until they mature in the female ovary, beginning at puberty. (Only one oocyte per month, on average, will complete this maturation process.) Oocytes that mature will enter meiosis II, but their development will remain arrested there until they are fertilized by sperm. An unequal meiotic division of cellular material leads to the production of three polar bodies from the original oocyte and one well-endowed egg. The egg can go on to be fertilized, but the polar bodies will be degraded. polar body meiosis ll spermatids polar bodies (will be degraded) egg

1st law - segregation of alleles Cells contain 2 copies (alleles) of each gene Alleles separate during gamete formation (meiosis) gametes carry only one copy of each gene Gregor Mendel worked with peas to discover exactly how traits are inherited. Principles hold true for all sexually reproducing organisms. Somatic cells are diploid with 2 copis of each gene. Gametes are haploid with only one copy of each gene.

Punnett squares show parental gametes and the genotypes of next generation Homozygous: BB and bb Heterozygous: Bb Possible genotypes and their probabilities Knowing that each gamete carries only one allele per gene allows us to predict what traits progeny will inherit. Punnett squares are one tool that makes it easy. Genotype of each parent on adjacent sides of the table. Then label each column and row with the allele that would be in their gametes. Here, father has A or a in his sperm and mother has A or a in each egg. Fill in table with allele from headings and this shows genotypes of potential progeny. Note that these are probabilities, not exact predictions. To determine genotype of AA vs Aa (same pheno if A is dominant over a), look at progeny. Figure 19.2

Law of Independent Assortment During gamete formation, genes for different traits separate independently into gametes Why? random alignment of homologues at Meiosis I Mendel’s second law: traits are inherited separately from each other. Ex. Hair color and hair curliness are controlled by separate genes and so children can have different combos of these traits from each parent. The reason is due to the way that chromosomes are lined up for meiosis when gametes are produced.

Chromosome behavior accounts for Mendel’s principles During first division of Meiosis, homologous pairs line up with each other. Closely = synapsis. 2 possibilities shown at top, with 4 xsomes. Blue = paternal, red = maternal origin of xsome. Both arrangements are equally likely. On left side, gametes have either all dad’s xsomes or all mom’s. On right side, each gamete has one xsome from dad and one from mom, although the four gametes are still not alike. Result is that an allele on xsome 1 will not necessarily be inherited with the same allele on xsome 2 as existed in the parent. I.e, dad’s curly hair and blond color plus mom’s straight black hair may produce child with curly black hair. Independent assortment of genes. Consider the number of combinations of xsomes possible with 23 pairs of homologues. Creates enormous genetic diversity among humans. Figure 9.17

Crossing over produces gametes with recombinant chromosomes Tetrad A B a b Crossing over A B a a B b A b Gametes Genes on the same chromosome tend to be inherited together = linked genes Crossing over produces gametes with recombinant chromosomes Second major source of genetic diversity is recombination. Result of physical cut-and-paste of xsomes. Occurs during prophase I of meiosis, when homologous xsomes are synapsed. Creates xsomes that contain some of mom’s genes AND some of dad’s genes. Xovers are common: every homologous pair has at least 2 xovers (1 per arm) and longer arms can have several. Typically, 30 xovers per xsome. Process is required for meiosis to proceed to next step. No xovers, no gametes. So, result is huge amount of genetic variation in human gametes. 6+ billion people, no two alike.

Incomplete dominance VARIATIONS ON MENDEL’S PRINCIPLES P GENERATION Incomplete dominance Red RR White rr Gametes R r an offspring’s phenotype is intermediate between the phenotypes of its parents Pink Rr F1 GENERATION 1/2 R 1/2 r Previous example showed alleles with dominant/recessive effect, such that dominant allele determined the phenotype. Only one B required to produce B trait. Allele b is recessive, usually due to mutation that makes a nonfunctioning protein or no protein. If alleles show incomplete dominance, the phenotype can be a blend of parent types, intermediate. Ex. Is flower color. One allele is expressed, but level of expression is reduced by second allele. Subsequent generations show that the genes themselves are not changed; red and white flowers are still possible. Human ex: hair curliness and hypercholesterolemia. 1/2 R 1/2 R Eggs Sperm Red RR 1/2 r 1/2 r Pink Rr Pink rR F2 GENERATION White rr Figure 9.12A

Incomplete dominance in human hypercholesterolemia GENOTYPES: HH Homozygous for ability to make LDL receptors Hh Heterozygous hh Homozygous for inability to make LDL receptors PHENOTYPES: LDL Most common genotype is HH, with receptors for LDLs, allowing cholesterol uptake into cells. Heterozygotes have reduced number of recptors and elevated levels of LDL (300 mg/L). Hh people with no receptors and very high LDL levels (600mg/L+) and high risk of atherosclerosis and heart attack at young age. LDL receptor Cell Normal Mild disease Severe disease Figure 9.12B

Many genes have more than two alleles in the population Ex. three alleles for ABO blood type in humans IA, IB, i Review ch on blood types. Alleles IA, IB are codominant, so both are expressed. Leads to Type AB blood. Allele i is recessive to both other alleles, so no expressed. Genotype I/I is Type O, no surface proteins. Multiple alleles is common in human populations. Patterns in ethnic groups show evolution and migration of human populations.

Polygenic traits - A single trait may be influenced by many genes Quantitative traits skin color, height, eye color Fraction of population Some traits are the result of several different genes (not alleles), such that there is an additive effect of each gene. With more genes, there are more categories of phenotypes (number of bars in the graph). Result is appearance of continuous variation in the phenotype, I.e., quantitative traits. Separate from environmental influences. Skin color, height, eye color. Amt of melanin in iris will reflect light differently, resulting in various eye colors. Skin pigmentation

Genetic traits in humans can be tracked through family pedigrees The inheritance of many human traits follows Mendel’s principles and the rules of probability Many human traits are controlled by single genes. Ex in slide. True for disorders, too. Cystic fibrosis, deafness, Tay Sachs. Hitchhiker thumb. Pedigrees used to predict potential disorders in children, help make reproductive strategy. Figure 9.8A

Family pedigrees are used to determine patterns of inheritance and individual genotypes Dd Joshua Lambert Dd Abigail Linnell D_ John Eddy ? D_ Hepzibah Daggett ? D_ Abigail Lambert ? dd Jonathan Lambert Dd Elizabeth Eddy Look at legend for standard use of symbols. Color indicates that the phenotype is present. Genotype is written underneath each person’s symbol. If genotype is known, phenotype can be assigned. Looking at progeny can reveal presence of alleles (genotype) in parents. Uncertain alleles are indicated with ? Trace analysis of this pedigree. If given only the phenotypes, be able to fill in the genotypes of each person. Often used to determine risk of cancer in individual. Could indicate that a person should have a genetic screening done for a particular gene (BRC1, 2; Colorectal cancer gene) or just make aware of risk. Dd Dd dd Dd Dd Dd dd Female Male Deaf Figure 9.8B Hearing

Inherited Genetic Disorders Most mutations usually involve recessive alleles Phenylketonuria, PKU Tay-Sachs disease Cystic fibrosis Normal Dd Normal Dd PARENTS D D Eggs Sperm DD Normal d d Dd Normal (carrier) Dd Normal (carrier) OFFSPRING If mutation makes a nonfunctional protein, or no protein at all, likely this is recessive because the normal allele on the homologous xsome will produce enough normal protein to prevent disease. Both parents must contribute the recessive allele to have any chance of a homozygous child (two recessive alleles) with the disease. Probability of disorder is 1/4 for every child of these parents. Doesn’t change for successive children. So, parents who know they both carry an allele for a particular condition can make choices. Some use IVF, then PGD (preimplantation genetic diagnosis) to select embryos without the disease alleles, then implant those in uterus. Some of these alleles are more common in the pop than people realize. Tay-Sachs is about 1/100, with those of Eastern European Jewish ancestry more likely to carry it. Currently, spreading throughout general pop, so not at all limited to this group. dd Deaf Figure 9.9A

A few are caused by dominant alleles Examples: achondroplasia, Huntington’s disease DOMINANT alleles always reveal their presence in the genome, although the timing may be delayed. Dwarfism is evident early; Huntingdon’s does not appear until 40s or so. Degenerative neuromuscular disease that is fatal. Challenge is that reproductive decisions have been made by that point, so children may inherit the gene before you know that you have it. Many families with history of Huntingdon’s choose genetic analysis, which has its own dilemmas: since there is no cure, do you want to know your fate? Figure 9.9B

Sex-linked disorders affect mostly males Most sex-linked human disorders are due to recessive alleles Ex: hemophilia, red-green color blindness These traits appear mostly in males. Why? If a male receives a single X-linked recessive allele from his mother, he will have the disorder; while a female has to receive the allele from both parents to be affected Figure 9.23A Sex-linked refers to traits that are the result of genes on the X xsome, not necessarily anything to do with gender. Since X and Y xsomes determine gender, anything else on those xsomes will be “sex-linked”. Draw out possible genotypes and phenotypes to show why males display these traits more often than females. Include punnett squares to show how all males from certain pairings will always have these traits. Some traits influenced by sex genes. Ex. Male baldness due to b/b genotype, causes early hair loss under influence of testosterone. Female w/ b/b will not show same loss pattern. Ex of environmental influence on gene expression. Note that environment is the cellular environment.

Pedigree Chart: Inheritance Pattern for an X-linked Recessive Disease Run through this pedigree to explain sex-linked genes. Carrier - person who has the gene but does not express the phenotype. In hemophilia, carrier must be female. If any male has the gene, it results in the disease. Figure 19.12

Czar Nicholas II of Russia A high incidence of hemophilia has plagued the royal families of Europe Queen Victoria Albert Alice Louis Carefully controlled matches resulted in hemophiliac Alexis. Changed the course of history. Alexandra Czar Nicholas II of Russia Alexis Figure 9.23B

Variations on Mendel’s Principles Codominance, multiple alleles Pleiotropy Polygenic traits Sex-linked genes Environmental effects Review these cases. Pleiotropy = one gene with multiple effects. Ex. Sickled cell anemia, in which altered hemoglobin causes multiple symptoms of anemia, kidney disease, heart attack, stroke. Marfan’s symdrome, w/ defective protein that causes weak connective tissue, esp in heart. Loose joints, large hands and feet. Heart problem only obvious under physical stress. Note that these effects are only present in particular environments (low oxygen pressure) Mendel’s first two laws hold true, with exception of linked genes.

Accidents during meiosis can alter chromosome number Abnormal chromosome count is a result of nondisjunction homologous pairs fail to separate during meiosis I Nondisjunction in meiosis I Normal meiosis II Nondisjunction = not separate correctly. Can happen during 1st or 2nd division. Result is gamete with extra xsome and gametes missing xsome. Usually lethal or much reduced viability. Gametes n + 1 n + 1 n – 1 n – 1 Number of chromosomes Figure 8.21A

Or sister chromatids fail to separate during meiosis II Normal meiosis I Nondisjunction in meiosis II Sometimes, eggs are still functional. With normal fertilization, can produce embryo with extra xsome. Gametes n + 1 n – 1 n n Number of chromosomes Figure 8.21B

An extra chromosome 21 causes Down syndrome The chance of having a Down syndrome child goes up with maternal age Risk increases, such that amniocentesis is recommended for mothers over 35 yrs. Risky procedure (1% MISCARRIAGE) so not routinely done. Figure 8.20C

Fetal testing can spot many inherited disorders early in pregnancy Karyotyping and biochemical tests of fetal cells can help people make reproductive decisions Fetal cells can be obtained through amniocentesis Amniotic fluid withdrawn Centrifugation Amniotic fluid Explain procedure and risks. Karyotype can be analyzed for gross abnormalities that change xsome structure. Not the same as looking for particular alleles = genetic testing. Fluid Fetus (14-20 weeks) Fetal cells Biochemical tests Placenta Several weeks later Uterus Cervix Karyotyping Figure 9.10A Cell culture

Some biochemical tests Chorionic villus sampling is another procedure that obtains fetal cells for karyotyping Fetus (10-12 weeks) Several hours later Placenta Suction Karyotyping Fetal cells (from chorionic villi) Faster procedure, less risk of miscarriage. Some biochemical tests Chorionic villi Figure 9.10B

Examination of the fetus with ultrasound is another helpful technique High-resolution ultrasound can reveal function of heart, kidneys, other organs. PGD uses only a few cells at most to determine if particular genes are present. PGD - Preimplantation Genetic Diagnosis genetic analysis of embryos from in vitro fertilization (IVF) before inserting into womb Figure 9.10C, D

Genes and Behavior Mechanism Product from gene-specific proteins Proteins have specific functions leading to phenotypes: hormones, enzymes, transport, neurotransmitters Complex traits such as behavior can be inherited. More often in humans, TENDENCY towards a behavior are inherited. Ex. Risk of alcoholism, depression, autism. Interaction with environment is critical component. ‘Falling in love? Perhaps.