Class Note for ANTHROP 301 with Professor Crews at OSU
Class Note for ANTHROP 301 with Professor Crews at OSU
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Date Created: 02/06/15
Heather Hampel Genetic Counseling HNPCC amp The American Founder Mutation October 27 2009 Health professionals with degrees and experience in medical genetics and counseling GCs provide supportive counseling to families serve as patient advocates and refer individuals and families to community or state support services GCs serve as educators and resource people for other health care professionals and for the general public Some counselors also work in administrative capacities Many engage in research activities related to the field of medical genetics and genetic counseling Breakdown of Primary Roles Clinical 83 Teaching Educational 54 Research 32 CoordinationAdministration 29 Careers in Clinical Genetic Counseling Prenatal 55 Cancer 39 Pediatrics 36 Adult noncancer 24 Specialty disease 14 Prenatal Patients Pregnant woman has a brother with cystic fibrosis CF and wants to know the chance that her baby will have CF too A pregnant woman with no family history of genetic conditions has just had an ultrasound that showed her baby has a birth defect Cancer Genetics Patients A 30 year old woman has a family history of breast cancer and wants to know her risk of also developing breast cancer A 22 year old man with thyroid cancer was recently diagnosed with Multiple Endocrine Neoplasia Type 2A He wants to know more about the condition and what it means for his future and his family Pediatric Patients A baby is born with multiple congenital anomalieslow birthweight heart defect and clubfeet among others and is referred to genetics for diagnosis A 2 year old child has been diagnosed with a metabolic disorder in the ICU after suffering an acute crisis Adult Patients A 35 year old woman whose mother had Huntington disease HD wants to know the chance that she will develop HD A 40 year old man has had high cholesterol since age 25 and a family history of early onset coronary artery disease I ypical patient routine The basics Obtain detailed personal and family medical history ReView available medical records Propose differential diagnosis Discuss features of possible hereditary syndromes EXplain genetics of syndrome Discuss testing process and risks ys benefits Outline management options Follow up with letterreferrals etc Other careers for genetic counselors Research clinical epidemiological laboratory Education Politics Salary UniVersity medical center mean salary is 51111 Starting median salary in our region is 42500 Colorectal cancer Microsatellite Instability Pathway and Chromosome Instability pathway CIN is 85 Why determine which CRC cases are MSI and which have LS All MSI CRC patients have a better prognosis MSI CRC patients MAY need different treatment in future LS patients at high risks for second primary cancers CRC and others LS patients have at risk relatives who could benefit from genetic testing Autosomal Dominant50 chance that if you have lynch smdrome that you will pass it on MSI is caused by a failure of mismatch repair MMR genes What is the American Founder Deletion A large gene deletion causing HNPCC ldentif1ed in at least 22 distinct families who thru genetic studies have been shown to be distantly related Through geneaology three families have been linked to the Clapp family The American Found Mutation is formed from the Founder Effect Which is where new people travel to an island etc and start a family The genes from those two individuals are passed on and only those genes Genetic Polymorphisms and Health Anthro 301 October 29 2009 Midterm ZNovember 12th Lynch Syndrome could be a single mutation that happened in one person HLAMHC Responsible for self recognition and antibody defenses Human Leukocyte antigen systemmajor histocompatibility compleX HLA in humans MHC in other mammals Present foreign antigens to Tlymphocytes to stimulate an immune response HLA System 6p21 Responsible for histocompatibility Tissue rejection typing All cells in the body have tissue antigens Every cell is marked with HLA proteins D markers are not on every cell On leukocytes Codes for glycoproteins In mice HLA is spread out over the genome 1419 chromosomes most on number 17 Concentrated on chromosome 6 in humans D antigens mark white cells the helper T cells are modified to be immune competent Autoimmune diseases are associated with the HLA system All the D loci have a subset of loci within them with their own alleles Some have over 100 known alleles 9 highly polymorphic 6p21 inclues about 100 transcribed units plus a lot of psedo genes Linear sequence HLA system is inherited as a haplotype One haplotype comes from each parent 6 major HLA loci More loci in this 115 million bp segment of DNA than any other place in the human genome class I HLA genes are AB and C Self markers A B and C genes code for glycoproteins Found on all body cels except erythrocytes rbcells This is why blood transfusions are possible Class H HLA genes are DP DQz and DR At least 4 loci for each serotype Each of these 6 major loci has 50200 known alleles DP DQz DR genes code for glycoproteins that are on Blymphocytes and macrophages Present antigens to Tlymphocytes to generate antibody manufacture Group I A thru G except DP DQz and DR Histocompatibilty markers on all cells SELECTION AGAINST HOMOZYGOSITY Group 2 macrophages WBC s carry D markers needed to reject foreign tissues and organisms Minimum of 6 million indiVidual haplotypes perhaps 33 million for AG alone Number of combinations would be this number squared or 36 million haplotypes for the human populations 1 in 167 people would have one of the same haplotypes by random assortment But different haplotypes segregate in different populations Forensic Applications of HLA Paternity ldentif1cation of the dead DNA fingerprinting of criminals Evolutionary biology Applications of HLA Relatedness of individuals Bottlenecks in prehistory Population affinities Uniqueness of inbred groups Disease susceptibilities and longevity Viral inserts 8 of the human genome DNA from human endogenous retroviruses HERVs 1000s Oldest 550 MY ago during vertebrate evolution Most recent HERVK113 about 200000 years BP Viruses were defeated by survivors but some were integrated into genome Because they infected gametes and were passed on to future generations Most are in noncoding regions Many are used as templates within the HLA system retroviruses are not like measlesinfluenza mumps Evolutionary biology Some are remolded into active proteins HERVs may provide defenses against exogenous Retroviruses May occupy docking sites on receptors used by ERV HLA Alleles and Diseases HLA associations with autoimmune diseases B27 increases the risk of ankylosing spondylitis Bone disease causes bone to turn to mush Arthritis bowl diseases Most carriers of B27 mutation show no disease Dr3 increases risk of type I diabetes Pancreatic beta cells are attacked by antibodies Prior viral infection with sequence similarity to proteins on pancreatic cells Dw2 multiple sclerosis Apolipoproteins Four types ABCll E and more Short proteins about 300 amino acids long avg length Transport synthesis and breakdown of lipids Three major alleles for apolipoprotein E E2 E3 E4 chromosome 19 locus E2 low cholesterol E3 moderate cholesterol E4 high cholesterol 9 late onset Alzheimers Mediterranean allele very low cholesterol High density Lipoprotein HDL Mainly apolipoprotein A A1 A11 HDL Good cholesterol Carries bound cholesterol to liver to be metabolized Collected excess cholesterol from cellsvessel walls for return to liver and disposal Delivers cholesterol to gonads for steroid hormones lnhibits monocyte adhesion to vascular walls lnhibits thrombin induced binding of fibrinogen to platelets lnhibits formation of foam cells Low Density Lipoprotein LDL not the worst cholesterol but a bad one lnteracts with LDL receptors on the liver no innate system to dispose of excess cholesterol the environment of evolutionary adaptation the environment that hominids evolved in had a low cholesterol Mainly contains apo B and E E IS IMPORTANTSS LDL BAD CHOLESTEROL DUDES Very low density Lipoprotein LDL contains mainly apo CH also found in HDL LDL Acts similar to LDL except even more atherogenic Chilomicrons low density fats transported from intestines to liver for metabolism Apoliprotein E4 Has only 1 cystine no disulfide bond lnteracts poorly with liver LDL receptors Favors plaque formation and atherogenesis Binds poorly with microtubules in the brain Associated with late onset alzheimers ages 70 Apolipoprotein E table 0 E2 in Yanomami have low fat diets in Amazon and high apo E4 E4 associated with heart disease and strokes in modern settings In tradiational setting E4 an advantage maintinas higher LDL in blood in low dietary fat setting High fat intake in modern settings high body fat Apolipoprotein E EM found only in one village near Milan Italy Allele associated with low cholesterol and CAD in a high fat intake setting Low LDL bad cholesterol Apolipoproteins are involed in cell surface interactions Associated with neurotransmitters lnteract with brain cells May promote lateonset Alzheimers Mutant LDL receptor on liver does not interact with apo E early death and heart disease E4 decreased in centenarians E2 higher Long lived people tend to have more E2 than E4 Familial Hypercholesterolemia High cholesterol in the blood due to mutant LDL receptor Liver receptors do not recognize protein cholesterol is not eXtracted from blood Stored as lipid plaques in eyelids kneeds hands Simple trait intermediate heterozygote CO DOMINANT Homozygous dominant for the mutinent cholesterol 700 mgdl fatty blood Heterozygous 350 mgdl treatment for high cholesterol thru lifetime Wild type homozygote recessive normal 20 to 30 years old 240 gdl now 170 mg dl nerve sheaths are made out of cholesterol November 3 2009 Familial Hypercholesterolemia Homozygous Dominant cholesterol 700 mg fatty blood Heterozygous 350 mgdl treatment for high cholesterol through lifetime Wild type homozygote recessive normal 20 to 30 year old 240 gdl Now 170 mgdl Example South Africa High frequency mutant LDL receptor in some groups Boers Dutch colonizers religious enclaves branching pattern from coast to interior for specific churches founder effect two brothers were church leaders passed gene on to many descendents Plasmaphoresis Cleans fat out of blood l o of all people in US carry mutant LDL receptor 50 of people treated at lipid clinics carry mutants P53 the antioncogene gene Discovered when searching for oncogenes in mice 1970s 53 Kilodalton protein Oncogenes genetic loci that lead to cancer BRCA 1amp2 RAS usually house keeping loci P53 was never observed to cause cancer Reexamined in 1989 found to associated with tumor suppression P53 Transcription factor that controls cell cycle and thereby halts development of cancer lnitiates DNA repair and apoptosis halts cell cycle cancer initiation multihit model Apoptosis of cells exhibiting abnormal growth 9 normal p53 knocked out 9 cancer neoplasm development series of 300 cancer patients 320 mutant p53 observed About 50 of all lung colon and bladder carcinomas have mutations in p53 ournal of NIH Research and Science named p53 the molecule of the year in 1993 Tumor suppressor protein Guardian of the Genome 17p131 about 393 aa length cellular tumor antigen with 3 domains transcription activation dna binding homooligomerization eXtension of dna Specif1c mutations yield specific cancers aa 249 bladder cancer hot spot for mutation highly conserved molecule in its functional domains humans 17 rats 10 mice 11 Observed in most sexual reproducing species Wild type p53 halts cell division at the point of DNA replication Wild type maintained no cancer develops mutation cancer develops Marks cells for apoptosis by initiating transcription of DNA cistrons coding for other proteins Apoptosis nontraumatic cell death Nucleus dissolves cellular DNA is cut into pieces of about 700 base pairs Macrophages ingest the DNA chunks and cellular debris Short halflife 9 20 min Mutant forms longer halflives 9 greater than 20 min half lives vary for proteins collagen structural 9 lifetime digestive enzymes 9 30 mins Neurotransmitters 9 instantaneously or immediately LiFurmani Syndrome children born heterozygous for mutant p53 tumor suppression is reduced develop tumors in early adulthood or earlier p53 also mutates Within somatic cells Porphyria Vampire s Disease Mutation in enzymes needed for heme production porphyrins are the main precursors of heme characteristics skin with little to no color aVoid sun to avoid severe risk of skin cancer gums retreat iron deficient mental disorders Garlic stimulates production of hemoglobin but makes prophyria painful Drinking blood as remedy in middle ages MedieVal Transylvania nobles lived in castles Peasants did not constant sun eXposure any porphyria patients would die young Nobles were protected by being able to stay indoors and live longer Legend of Count Dracula Alcohol Dehydrogenase Enzymes secreted by stomach lining and liver that catalyze the oxidation of alcohol ethanol to acetaldehydes Two major phenotypes fast or slow codominant polymorphism Heterozygotes are intermediate US and Europe 6 are slowslow Asia 90 are slow slow Alcohol consumption anerse curvilinear association with CHD coronary heart disease risk Alcohol raises blood HDL Homozygotes for ADH3 allele slower alcohol metabolism greatest risk reduction Significant decrease in risk for CHD 1 drinksday Moderate consumption lowers CHD risk Xeroderma Pigmentosum Australia and South Africa highest frequencies Xeroderma Pigmentosum Genetic disorder of DNA repair in which the body s normal ability to fiX mutations caused by UV light is disabled Skin malignancies basaliomas skin cancers in endothelial cells Nucleotide excision repair enzymes are faulty Homeobox Genes A stretch of DNA that regulates development and determines the body plan in animals Plants have homeobox genes but different H0meobox genes are linearly arranged and sequentially turned on and off during development to make body parts Homeobox genes are inherited as a haplotype humans have 4 clusters chromosome 2 7 12 17 About 180 base pairs HOX cluster of genes determine the placements of segments of the body Sickle cell Anemia and Other hemoglobinopathis November 3 2009 Hemoglobin Hb Protein found in RBC contains Fe iron binds oxygen and transports to body tissues binds carbon dioxide for return to the lungs consists of 4 polypeptide chains 3 alpha 2 beta and 4 Fe molecules heme is the Fe molecules and the proteins Anemia low oxygen delivered to tissues abnormal Hb reduction in the RBC numbers Hb of 98 of human adults 2 alpa chains 141 amino acids long 2 beta chains 146 amino acids long different hemoglobins are made at different points in the human lifespan Fetal Hb 2 alphachains 2 gammachains 146 amino acids long Less than 1 of adults have fetal Hb Child Hb 2 alpha chains 2 deltachains 146 amino acids long Nearly 2 of adults have child hb In adults fetal Hb and child Hb do not transport oxygen as efficiency as adult Hb Alpha chain in Hb More highly conserved Presumably important in sustaining life 2 Loci 4 alleles code for the alpha chain Likely basis for all other chains Beta gamma and Delta chains 1 locus 2 alleles for each chain Arranged linearly on chromosome lnherited as a haplotype Slightly different base pair sequences likely arose by gene duplication followed by mutation Scattered along this haplotype are multiple pseudogenes short noncoding duplications Turned on off sequentially during normal development gamma chain gene turned on then off delta chain turned on then off f1nally beta chain gene is turned on Thalassemias Hereditary form of hemolytic anemia Reductions in Hb chain synthesis Alpha ad beta thalassemias Alphathalassemias too few achains betachain tetramers carry oxygen poorly common in malaria regions mediterraniean and Africa deletions but also have extensionsframe shift mutations over 80 known mutations Major both alleles at 1 or 2 loci deleted homozygous clinical symptoms Minor normal gene and a deleted gene at 1 or both loci heterozygous clinical symptoms may not be penetrant degree to which the genotype shows in the phenotype Betathalassemias too few beta chains tetramers of the alpha chains common in malaria areas of the Mediterranean most are point mutations nonsensedeletions duplications also about 150 mutations are known Thalassemias beta thalassemias often fetal type of anemia RBCs abnormally large macrocytic anemia low Hb content per cell Poor transport of oxygen facial and skull bones are thick Most mutations are not polymorphic ie occur at lt10o frequency Still have significant variation in Hb Coole s Anemia fetal thalassemia mutations that cause cooley s Anemia are polymorphic about 10 frequency seVere betathalassemia most thalassemia alleles are thought to be neutral or transitional neutral mutations may build at high frequencies in isolated inbreeding demes Associatinos with Malaria Sickle cell allele Glucose6phosphate dehydrogenase g6PD deficiency Xlinked Hemoglobin c allele thalassemias Sickle Cell Anemia First disease identified by electrophoresis Heterozygotes had 2 spots of betachain Hb Dominant and recessive homozygotes had only one Three genotypes SS normal prone to malaria Ss carrier anemia susceptible to malaria but not as bad as SS fair poor altitude hypoxia ss sickle cell disease die from ss disease before reproducing Sickle Cell Hb Substitution mutation at the 6th amino acid in the betachain Glu glutamic acid no charge 9 yal valine charge Hemoglobin C Disease Substitution mutation at the 6th amino acid in the betachain Glu 9 Lys lysine charge causes a milder form of anemia than sickle cell trait S and C hemoglobins Both make RBC sickle reduce their ability to carry oxygen Reduce K potassium content in RBC malarial parasite reproduces less efficiently reducing malaria load on body Malarial Parasites Different parasites all protozoans Transmitted by different species of mosquitoes Different Hb variants are more effective against different kinds of malarial parasites Plasmodium falciparum most common malaria in the world Annual death toll 69 million people does not kill immediately years to decades long term survival that becomes more and more debilitative multiple opportunities for transmission 80 of modern human infections 7 90 deaths Plasmodium vivaX most frequent and Widely distributed in the past both Hbs and Hbc protect against both P falciparum and P vivaX malaria Duf blood group Null allele Fyquot Monomorphic in Plasmodium vivaX areas RBC lacks Duffy antigens attack sites for Plasmodium vivaX duffy null allele not found in Europeans 100 in W Africa and malarial environments Frequency of Fy85 in African Americans 15 admixture with Europeans Fact Heterozygote carrying both an allele for sickle cell anemia and an allele for hemoglobin C disease has a better fitness than a heterzygote for either alone Ecology of MalariaCarrying mosquitoes Fly between 47 feet altitude Common by bodies of still water most active at dawn dusk Cultural protections away from water live on a hill house on stilts work in midday or at night SS individuals High malaria parasite load parasite is reproducing rapidly in them Die younger and more frequently from malaria More debilitation from chills fever and sweats have decreased energywork capacity copulate less frequently Malaria fever increased miscarriages kills sperm lrregular ovulationmenstrual cycling Fewer people live to adulthood to help in child rearing Ss Low parasite loads parasite is reproducing more slowly die older and less frequently from malaria because of less debilitation from chills fever and sweats more work capacity copulate more frequently Decreased malaria fever fewer miscarriages higher sperm counts more regular ovulation Ss Least afflicted by malaria shortest lifespan f1tness is 0 selection is 1 Do not surive to reproduce Sickle cell mutation probably occurred multiple times before malaria environment No selective pressure no increase in frequency mutations do not respond to environment Vocabulary Isoproteins Different forms of the same protein in different individuals eg isoenzymes Zoonosis disease that has gone from being in animals to being in humans malaria hiv avian flu swine flu chicken pox Vector transmits from one host to another mosquitoes for malaria Pandemic everyone is eXposed because the disease is so prevalent in a particular geographical area eg malaria in subSaharan Africa Epidemic disease comes in a wave infects all susceptible people then leaves eg in uenza Episodic Disease occurs in episodes over time eg black plague Ecology of Malaria Pre6000 BPE November 5 2009 Malaysian Agricultural Complex was being practiced in SE Asia Swidden agriculture of root crops and pulses Yams taro cassava sorgum and millet Africa lush rain forests many animals People were huntergatherers with very low population densities mainly lived in scattered groups along waterways Ecology of Malaria 6000 BPE Millet cultivation appeared in Africa Forests were cleared for planting Stagnant pools of water accumulated in cleared fields Human population density increased Settlements became larger and more stable Mosquitoes new host By 5000 4000 BP malaria was widespread among people in Africa Sickle cell and hemoglobin C mutants advantaged in now malarial areas lncreased in frequency of these alleles due to protection against malaria FavismG6Pd Deficiency glucose6phosphate dehydrogenase on pathway of glucose metabolisms G6PD is X Linked def1ciency in G6PD RBCs carry less oxygen Malarial parasites need oxygen potassium and phosphate G6PD deficiency protects against malaria Favism found in malarial areas of the Mediterranean especially common in Sardinia and Sicily Mutation Founder Effect People with favism react negatively to quinine A drug for treating malaria People with favism aren t able to metabolize fava beans Staple in the Mediterranean diet Hemolytic crisis when beans are eaten RBCs stop carrying oxygen aggregate and being dying Malaria Major selective agent for Sickle cell anemia probably the oldest mutation Hemoglobin C disease seems to be replacing sickle cell anemia now alphathalassemia and betathalassemia favism G6PD deficiency Strongest Facts Sickle RBCs will aggregate around a cholesterol plaque in blood vessels Under crisis capillaries and arterioles will rupture Hypoxic conditions will cause a crisis Sickle Cell Anemia Pleiotropic Effects 1 Destruction of sickled RBC leading to anemia 2 RBC clumping and interference with circulation 3 Collection of RBC in spleen with subsequent spleen enlargement Sickle Cell Anemia It was known that blacks were prone to be carriers of sickle cell anemia so they were prohibited from ying airplanes during WWI but did late in WWII Feared they would undergo a hemolytic crisis at altitude The success of the Tuskegee airmen during WWII changed this attitude Inbom Errors of Metabolism IEM November 5 2009 IEM inborn errors of metabolism genetic variability in how we metabolize our environment Mutations that change the structure and or function of enzymes Form of human variation IEM Enzyme mutants isozymes present form birth Alter biochemistry of metabolism lsoenzymes differ in their primary structure in amino acid sequence Metabolism sum of how enzymes convert environment to self and maintain soma body environment anything that comes into your body Amylases Nonspecif1c enzymes digest a variety of carbohydrates CHOs 1p21 inactivated by gastric acid of stomach Secreted in saliva begins CHO digestion Saliva acts as a disinfectant because it contains amylase and other molecules antibodies enzymes Amylase also digests sugars on microbes spit may clean hands better than water Multiple amylase isoenzymes in humans General function of enzymes Majority of mutations likely neutral Mutant broad specificity enzymes little effect on phenotype Function can be assumed by another enzyme Digestive enzymes broad specificities Biosynthetic pathway enzymes tend toward narrow specificities Enzymes Most enzymes producing inborn errors of metabolism are highly substrate specific Two categories of enzymes 1 Anabolic build things up 2 Catabolic Breaks things down IEMs 1 missing or defective enzymes most common cannot process substrate within body eg PKU 2 Loss of degradative pathway Cannot get rid of substrate eg Tay Sachs disease sphingolipids build up 3 Errors of absorption or reabsorption eg cystinuria build up of cystine 4 Coenzyme defects mutation prevents enzyme compleX from forming a Coenzymes vitamins metals proteins b Must attach to a polypeptide chain to make active enzymes IEM alter metabolic pathways Avoid IEM s by 1 Alternative pathway Amylase use alternative enzyme or take longer 2 Rid body of substrate Excrete 3 Detoxify Render substrate benign or reduce toxicity 4 Find alternative source for a product you need Generally rare Most lethal prior to birth Effect may show several metabolic steps beyond the enzyme defect Alternative metabolic pathway IEM may not be seen Most IEMs are recessive traits Heterozygotes often show incomplete penetrance NQ WH WN Usually primary errors of DNA Symptoms may not be directly related to error No Phenylalanine PKU buildup of phenylpyruvic acid PKA 8 IEM Strong selection against parents Large range of variation PKU Incomplete penetrance pp 50mg Phe100ml plasma high amount of Phe Pp 10mg Phe100ml plasma incomplete penetrance of recessive allele PP 1mg Phe100ml plasma normal amount of Phe in blood Heterozygote 12 phenylalanine hydroxylase activity intermediate phenotype Redundtant system 2 normal alleles not needed Enzyme activity of PP genotype is more than needed Heterozygote has adequate enzyme Pleiotropic Effects CNS neurons die in infantschildren Mental retardation and low IQ Motor system abnormalities Depressed melanin formation light skin and hair Deposit phenylpyruvic acid into joints mimicking arthritis PKU Phe and phenylpyruvic acid build up in blood Phe filtered by kidney Phe reabsorbed build up of toxic metabolite Rare autosomal recessive disease 110000 people What is the frequency of the recessive allele of the dominant allele of the heterozygote frequency PKU QAZ 110000 0001 requency of recessive genotype pp and recessive phenotype Qsqure root 0001 PKU in Celtic Populations Frequency in 2510000 Recessive allele freq 05 Heterozygote frequency 095 May be heterozygous advantage in Celtsl No detrimental effects in heterozygotes lighter skin solar radiation More Phe in blood less converted to Tyr not making as much melanin In northern latitudes lighter skin Allows for greater vitamin D synthesis by UV PKU allele entrenched in Celts mutation of founder s effect Northern latitudes Vitamin D increases absorption of calcium and decreases rickets in children In all states but two newborns are screened for PKU now only Arkansas Test accurate and those affected are easily treated Federal subsidy for Phe free diet Albinism Melanin is not properly formed Varieties of albinism different loci Different sizes shapes and darkness of melanin Sexual selection for albinism among the Hopi Indians Culturally yalued phenotype Albinism Loci Three different loci cause albinism 1 TyrosinasenegatiVe lack of tyrosinase Tyr not formed into melanin 2 TyrosinasepositiVe tyrosinase is present so the biochemical block is somewhere else Make Tyr from phenylalaine but no melanin 3 ocular albinism only in the eyes eyes are pink Albinos are blue eyed and see poorly at night blue eyed see well at dawn and dusk Brown eyed see well at night and poorly at dawn and dusk If the genotype of 1 ttAA and the genotype of 2 TTaa Two albinos could give rise to a normal child Per se is not fatal Albinos prone to melanomas skin does not block UV radiation Albinism allele frequency 01 Melanin is on phenylalanine metabolic pathway Same pathway as epinephrine and norepinephrine associated with fight or flight adrenaline Tyrosine Tyrosinosis build up of tyrosine Tyrosine on pathway to 1 Melanin 2 Thyroxin 3 Epinephrine and noepinephrine Neurotransmitters involved in stress responses Too much of these substances damages neurons Cretinism lodine de ciency goiter enlarged thyroid lnsufficient iodine and thyroid enlarges in attempt to make more thyroxin Pleiotropic traits 1 Stunted growth 2 Deficiency of bone mineralization 3 Mental retardation 1 Iodine or thyroxin prevents cretinism Occurs in high frequency in the New Guinea highlands Alkaptonuria Not a serious disease in youth OXidation of homogentisic acid in urine black pee disease ocranosis Defect in homogentisate 1 2dioxygenase Builds up and is excreted in urine turns black upon eXposure to the oxygen Excess homogentisic acid accumulates in joints particularly fingers and toes causing painful arthritis Urine is sterile unless one has UTI Urinary tract infection Used to disinfect wounds for centuries Confederate women saved urine and processed it into potassium nitrate for the war effort Tay Sachs Disease Hexosaminidase A deficiency GMZ gangliosidosis Chromosome 15 HEXA gene exon 11 mutation 1278insTATC Gangliosides are fatty acid derivatives sphingolipids active in signal transmission Hexosamindase A aids in recycling of sphingolipids Nervce cells of brain Block neurotransmission generation of nerves cells eventually burst Tay Sachs Disease Mental retardation neurons become distended Developmental reversion loss of motor function blindness cherryred spots on retina symptoms begin around 1 year after birth Death occurs by age 5 tay Sachs alleles in all population 1300 particularly high in Ashkenazi Jews 127 130 160 came to us in 1880s 1950 from Poland and Russia Ashkenazi Jews 1 in 3600 are homozygous recessive Cajuns 130 160 q Irish Am 150 q Heterozygote advantage Ghettos of Europe High incidence of tuberculosis and typhoid fever Concentrated populations lnfectious disease easily transmitted 1910 Philadelphia rabbi began keeping mating records of his congregation would not approve marriages between families among tay sachs family members Practice spread to synagogues along east coast Today Tay Sachs nearly eliminated from American Jewish population All descendents of Ashkenazi Jews in US are tested for hexosaminidase A deficiency Orthodox Jewish Dor Yeshorim anonymous screening program Evolutionary Biology Both PKU and tay Sachs reduce parental fitness Nine months maternal investment in utero Up to 5 years Parental Investment P1 in baby Heterozygote advantage Finishing past lecture November 10 2009 Mucopolysaccharaidosis Glycosaminoglycans Glocosaminoglycans are long chains of CHOs Found in joint uids Help in forming bone cartilage Lysosomal storage disease Autosomal recessive disease affecting collagen Collagen most common protein in body 25 Currently 28 named forms Mucopolysaccharidosis Mucopolysaccharides associate with collagen are not brown down in lysosomes One of 11 lysosomal enzymes dysfunctional Mucopolysaccharides build up in sells progressive cellular damage bone muscle nerve cells 9 death Cystinuria Autosomal recessive disease only aa with sulfur 1st metabolic disease studied scientifically Due to inadequate reabsorption after kidney filtration Cystine becomes excessively concentrated in urine bonds With itself preciptates out of solution as crystals forms kidney stones painful in kidney bladder and ureters other aa do not crystallize 1 10000 very rare compared to normal kidney stones m Autosomal recessive disease of purine and uric acid metabolism Ben Franklin Henry VIII Isaac Newton Sodium urate uric acid crystals accumulate in the joints and tendons inflammatory reaction causes painful metabolic arthritis deposits increase in size and burst through skin as sinuses Exude chalky White material we don t make vitamin c 1st disease of excess identified Egyptian mummies and Roman Gladiators Purine generator is stuck on will not respond to feedback inhibition Purine includes DNA bases adanine and guanine excess purines are metabolized to uric acid Enzyme glutamine PRPP amino acid transferase overactive Makes excess purines metabolized to uric acid Coenzyme defect Symptom of diabetes and metabolic syndrome Blood flows more slowly at eXtremities particularly at big toe most common symptom is pain in big toe m Humans and guinea pigs cannot make vitamin c scurvy before citrus fruits on sailing ships Uric acid replaces vitamin C metabolically Overuse of vitamin C gt uric acid Genetics and Ancestry Identifying susceptibility to Diseases November 10 2009 Race biologically subgroup in a species that is genetically more different than others Phenotype vs Genotype m is based on socially defined phenotypic classification Skin color morphological features cranial social classes Ancestry is based on a genetic classification Haplotypes YChromosome mtDNA Ancestry Information Markers AIM Race has been defined as Demes local breeding populations Geog139aphical Race Large population groups occupying entire continents AfricanAfrican American Darkskinned individuals Encompasses a broad genetic heterogeneous cluster of thousands of populations genetic miXture from Europeans is 25 White Lightskinned individuals Typically of European origin Millions of people spread throughout the world Heterogeneous group who possess certain points of the genetic array dispersed throughout Europe Does race define an individual s genome ie genetic makeup Skin color is dispersed according to ultraviolet radiation by latitude Example of Sociallv De ned Phenotvpic Classifications Skin Color Melanin blood keratin bilirubin Factors that determine skin color Amount of melanin and keratin Closeness to surface of blood vessels Skin thickness Number size color and shape of melanin granules prod by melanosomes Spectrophotometer used to measure blue red and amber light reflected by the skin the curves for European light and African dark will not overlap there is a dip in the curve at 550nm for light skinned individuals because they absorb blue light Four diallelic and codominant loci equivalents determine skin color Probably hundreds of loci that cause small effects on skin color 70 o of skin color is due to genes 30 is due to environment Skin color is not a marker for continent of origin nor is it useful in determination of disease susceptibility Skin color does however define a class that fits our preconceived images of inequality Socially defined phenotypic classifications ie race cannot be used to defineidentify the genetic traits an individual or a population possess Anthropology and human biology also reinforces this concept Biological race does not EXiSt but social race does eXist What is ancestry Genetic based description of an individual s or population s ancestral background Constructed through studying the genomes that compose a population Documents the genetic diversity of individuals Within a population therefore document the genome for a population Geographic ancestry Commonality of alleles and frequencies shared by peoples of the same area Crews and Gerber 2008 Genetic mechanisms leave their signatures on the DNA of populations and descendents by introducing local allelic variants and unique populationspecific genes Why is Ancestry Important Biomedical studies Racial typing has occurred within the field of biomedical research Hypertension diabetes cardiovascular disease Suggestion is that documenting the ancestry of individuals will provide an adequate platform for determining disease risk as well as treatment Biodiversity in Human Populations Sequence variation exists within and between populations 95 of human genetic variability is within populations 5 of human genetic variability is between populations Results from a broad sharing of genes throughout the human gene pool Example Southern African tribes differ at specific loci eg HLA systems just as they differ from equivalentsized groups living over 2000 miles to the northwest A lack of concordance of trait distribution Genetic variation is not randomly distributed Clinal distribution A distribution of frequencies that show a systematic gradation over space different groups express varying degrees of a trait genetic differences between groups are in the process of breaking down Migration and intergroup mating lndividuals are likely to have ancestry that is a mixture of different groups Allele Frequencies provide the genetic markers that distinguish between populations Small fractions of SNP differ among the world s continental population groups Older alleles more common across many populations ancestral alleles Newer alleles exhibit a low frequency and are localized derived alleles Haplotypes Over several generations segments of ancestral chromosomes in an interbreeding population are shuf ed through repeated recombination events Some segments occur as regions of DNA sequences that are shared by multiple individuals There are regions that are not broken up by recombination and are separated by places where recombination has occurred These are the haplotypes WA population of subproups exhibiting different allele frequencies Example European males mating with indigenous women Example FY null allele of the Duffy blood type in WestAfrican populations USrepresents a melting pot How far back does your family tree go in the US Think about the amount of genetic varation that came into the US when migration occurred Genetic blender Sociopolitical history of the US Slavery and segregation 7 increasedecrease How does knowing the geographical ancestry of an indivudla and or population in uence biomedical research and clinical applications for treating disease Haplotypes The use of haplotypes can identify populations that are at high risk for a particular disease HLA haplotypes and diabetes Jewish women and breast cancer Tay sachs and east coast Hasidic Jews Y chromosome Blood groups Human variation can be highly signi cant in the determination of disease susceptibility and treatment thereafter in terms of understanding how human variation is patterned and what it means variations re ect race but patterns and processes of human evolution interaction wit the environment and population movements
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