Insights from The Human Genome   Project about Risk of Disease          Toby G. Rossman, Ph.D.The Nelson Institute of Envi...
In 2003, scientists in the Human Genome Projectobtained the DNA sequence of the 3 billion basepairs making up the human ge...
THE HOPE:
Genes and The GenomeGenes are made of DNA and provide the directions forbuilding all of the proteins that make our bodies ...
Introduction to DNAA double helix (2 strands) with asugar-phosphate backbone.Attached to each sugar are oneof 4 “bases”: A...
What DNA does   DNA is the genetic material   within the nucleus. It is manyDNA is the genetic material   genes long.withi...
The “Central Dogma” of biology      DNAstores all information                                                             ...
The Genetic CodeThe genetic code is universal. All known organisms use the same genetic code. (Unity of life on earth; we ...
DNA is packed into chromosomes (highly condensed)
Genes are present both in the nucleus and in mitochondria      Chromosomes located in cell nucleus                        ...
An important technique: Hybridization Heating the cellular DNA will separate the 2 strands. You can then identify a piece ...
Painting the human chromosomes               Chromosome painting
A pair of homologous chromosomes (one from father and one from mother)                          Most genes are in the 23 p...
Some important lessons from the Human              Genome Project• The human genome is nearly the same in all people.We ar...
Only a small % gets translated into protein                                              NEXT                             ...
The DNA in a gene is interrupted. It is not all expressed.             Exons are expressed; Introns are removedAlternative...
What is all that DNA for?It turns out that 90% of the genome is actively transcribed into RNA. Although initially dismisse...
Genetic variation      Single nucleotide polymorphisms (SNPs)• Our genes are >99.9% alike (unless we are identical  twins)...
Understanding SNPs• Most variations are meaningless and do not affect ourability to survive or adapt.• For example: silent...
There are other types of genetic variation besides SNPsEleanor Rigby picks up the rice in the church. (Original sequence)E...
Gene duplication: A major event in evolutionGene duplications produce copy number variations (CNV) inhumans
Copy number variation (CNV)Copy number for amylase-1 gene is higher in populations with a starchy diet.                   ...
How different are human beings from one another? Differences in SNPs: about 10 million (~3/1000 bases) Large deletions a...
Risk Factors for Disease   A risk factor increases your risk of developing a disease   or health problem.                 ...
SICKLE CELL ANEMIA       An example of a single gene disease• Caused by a mutant allele h of a hemoglobin gene H.• 1/500 b...
Sickel cell anemia is caused by a single base change (SNP)                    Fig. 11.2
Some other genetic disorders caused by single genesDisorder                    Incidence (US)                    SymptomsC...
Complexities in single gene diseases: Cystic FibrosisCystic fibrosis (CF) is caused by an autosomal recessive mutation int...
Polygenic inheritance                  The Harder cases• These underlie some of the more clinically important  human disea...
Body Mass Index (BMI)• At least 17 genes interact to control body weight: Genes  that affect how much we eat, metabolic ra...
Breast cancer risk differs in different countries: Heredity or Environment?       US
Breast cancer risk cannot be entirely genetic.For example, diet, obesity, radiation exposure, and alcoholuse influence ris...
Another example: stomach cancerHigh incidence in Japanese men in Japan, but lower in Hawaii
Example of multifactor causation: breast cancer   or
Other inherited cancer syndromesSyndrome                              Primary tumors           Other tumors/traitsDominant...
Chemical carcinogens often cause DNA damage which   leads to mutations if the damage is not repaired                      ...
DNA repair defect diseases
Involvement of BRCA1 in DNA repairProteins known to bind to BRCA1’s BRCT domains—such as Abraxas, BACH1, and CtIP—are all ...
2007: The Year of GWA StudiesPennisi E, Science 2007; 318:1842-43.
THE NEWEST METHOD FOR GENETIC ANALYSIS:    Genome-Wide Association Study (GWAS)GWAS is an approach that involves rapidly s...
The Gene Chip (microarray)
Microarray chipsOligonucleotide probes representing manygenes are spotted in an array.
Types of microarraysComparative Genomic Hybridization (CGH): for genomic gains  and losses or for a change in the number o...
Genome-Wide Scan for Type 2     Diabetes in a Scandinavian Cohort:                SNP resultsttp://www.broad.mit.edu/diabe...
Type 2 DiabetesGWAS have accelerated the identification of type 2diabetes susceptibility genes. There are now at least 19 ...
GWAS for SNP Associations with Myocardial Infarction show hot region                on Ch 9Samani N et al., N Engl J Med 2...
GWAS for Age-Related Macular             DegenerationKlein et al, Science 2005; 308:385-389.
Wellcome Trust GWAS of Seven DiseasesWTCCC,Nature 2007;447:661-678.
BIG SURPRISE: Most SNPs associated withdisease susceptibility are in introns and intergenic positions!!
Unique Aspects and problems of GWAS• GWAS permits examination of inherited genetic variability  at unprecedented level of ...
Further Reading (and some criticisms)Taft et al., Non-coding RNAs: regulators of disease. J.Pathology 220:126-139, 2010Rob...
WebsitesCDC, Office of Genomics and Disease Preventionwww.cdc.gov/genomics/public/famhist.htm"DNA Interactive" Site from C...
Some other things besides genes are important
Founder EffectsOccur when a population is established by a small number ofpeople. A mutation in one of the founders become...
Steps in Chemical Carcinogenesis (also radiation)
HAPMAPTesting all of the 10 million common SNPs in a personschromosomes would be extremely expensive. Thedevelopment of th...
Diseases and Traits with Published GWA Studies (n = 76, 11/17/08)• Macular Degeneration          • Lipids and Lipoproteins...
Sci cafe humangenome&health
Sci cafe humangenome&health
Sci cafe humangenome&health
Sci cafe humangenome&health
Sci cafe humangenome&health
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  • Figure 2.3 The human genome contained in every cell consists of 23 pairs of chromosomes and a small circular genome known as mitochondrial DNA. Chromosomes 1-22 are numbered according to their relative size and occur in single copy pairs within a cell’s nucleus with one copy being inherited from one’s mother and the other copy coming from one’s father. Sex-chromosomes are either X,Y for males or X,X for females. Mitochondrial DNA is inherited only from one’s mother and is located in the mitochondria with hundreds of copies per cell. Together the nuclear DNA material amounts to over 3 billion base pairs (bp) while mitochondrial DNA is only about 16,569 bp in length.
  • How many SNPs were done?
  • Sci cafe humangenome&health

    1. 1. Insights from The Human Genome Project about Risk of Disease Toby G. Rossman, Ph.D.The Nelson Institute of Environmental Medicine NYU-Langone School of Medicine
    2. 2. In 2003, scientists in the Human Genome Projectobtained the DNA sequence of the 3 billion basepairs making up the human genome.The significance of this work to our health is anongoing project.
    3. 3. THE HOPE:
    4. 4. Genes and The GenomeGenes are made of DNA and provide the directions forbuilding all of the proteins that make our bodies function.Genes are passed down by parents to their offspring.The Genome is the sum total of all genetic material (DNA)in a cell.
    5. 5. Introduction to DNAA double helix (2 strands) with asugar-phosphate backbone.Attached to each sugar are oneof 4 “bases”: A, G, T, CBase pair:C always pairs with GA always pairs with TThe sequence of the bases (e.g.:AATGCCCTGAACGTT) contain theinformation (genetic code).
    6. 6. What DNA does DNA is the genetic material within the nucleus. It is manyDNA is the genetic material genes long.within the nucleus. Replication DNA is replicated before a cellThe process of transcription divides. Each daughter cellcreates an an identical copy. receives RNA using DNADNA information. Transcription The DNA in a gene is transcribedThe RNA leaves thecopy, using to create an RNA nucleus. information from one DNA strand. RNA The process of translation takes RNA leaves the nucleus. The place in the Nucleus cytoplasm. Translation In the cytoplasm, the RNA is I creates a protein using translated to create a protein RNA information. Protein using RNA information. Cytoplasm
    7. 7. The “Central Dogma” of biology DNAstores all information transcription mRNAcarries the messageCodon = 3 bases translation Protein A protein is a string of amino acids
    8. 8. The Genetic CodeThe genetic code is universal. All known organisms use the same genetic code. (Unity of life on earth; we are all related).The genetic code is degenerate. Some codons encode the same amino acid. e.g. GGU, GGC, GGA, and GGG all encode glycine. Degeneracy is mostly at the third base of the codon.Some codons have additional functions. AUG encodes methionine, but is also a start codon. UAA, UAG, and UGA do not encode an amino acid. These codons signal termination of the protein (stop codon).
    9. 9. DNA is packed into chromosomes (highly condensed)
    10. 10. Genes are present both in the nucleus and in mitochondria Chromosomes located in cell nucleus 1 chromosome in Autosomes mitochondria (hundreds of copies in cell cytoplasm) 1 2 3 4 5 6 7 8 9 10 11 12 Mitochondrial DNA 13 14 15 16 17 18 19 20 21 22 X Y mtDNA Sex- 16,569 bp Nuclear DNA 3.2 billion bp chromosomes Inherited only from mother
    11. 11. An important technique: Hybridization Heating the cellular DNA will separate the 2 strands. You can then identify a piece of DNA by hybridization, using a “probe” of the complementary strand (at least 12 bases). This also works with RNA. HOTCOLD
    12. 12. Painting the human chromosomes Chromosome painting
    13. 13. A pair of homologous chromosomes (one from father and one from mother) Most genes are in the 23 pairs of chromosomes in the cell nucleus. p Chromosomes contain thousands of genes. SOME DEFINITIONS Gene – unit of DNA information about a trait Alleles – slightly different versions of a gene Q Homozygous: both alleles are the same Heterozygous: the alleles are different
    14. 14. Some important lessons from the Human Genome Project• The human genome is nearly the same in all people.We are >99.9% alike.• Only about 1.5% of the human genome containsgenes that are translated into proteins.• Most of our DNA is transcribed into RNA, but nottranslated.
    15. 15. Only a small % gets translated into protein NEXT SLIDE
    16. 16. The DNA in a gene is interrupted. It is not all expressed. Exons are expressed; Introns are removedAlternative splicing of exons allows more than 1 protein from each transcript exon intron exon intron exon intron exon EXON = expressed INTRON = not expressed
    17. 17. What is all that DNA for?It turns out that 90% of the genome is actively transcribed into RNA. Although initially dismissed as “junk DNA”, recent evidence suggeststhat many of the RNAs transcribed from this DNA play major biologicalroles in control of gene expression, cellular development andmetabolism.For example:The Human Genome encodes only ~20,000 protein-coding genes. Butwe have about 100,000 different proteins! Alternative splicing yieldsmany more than 20,000 proteins. RNA molecules may help controlwhich splicing event occurs. We are at the tip of a very large iceberg!
    18. 18. Genetic variation Single nucleotide polymorphisms (SNPs)• Our genes are >99.9% alike (unless we are identical twins).• Gene sequences can differ at a single base (called single nucleotide polymorphism or SNP).• The human genome has at least 10 million SNPs.
    19. 19. Understanding SNPs• Most variations are meaningless and do not affect ourability to survive or adapt.• For example: silent mutations in DNA, which change theDNA, but do not change the amino acid the DNA codesfor.• Other mutations may change the amino acid sequence ofa protein, but not the overall function of that protein.• Some variation leads to disease. Single-gene disordersinclude sickel cell anemia, cystic fibrosis and Huntingtondisease.
    20. 20. There are other types of genetic variation besides SNPsEleanor Rigby picks up the rice in the church. (Original sequence)Eleanor Rigby picks up the lice in the church. (SNP)Eleanor Rigby picks up the church. (deletion)Eleanor Rigby picks up the rice and beans in the church. (insertion)Eleanor Rigby picku pt her icei nt hec hurch. (-1 frameshift)Eleanor Rigby picks hcruhc eht ni ecir eht pu. (inversion)Eleanor Rigby picks up the rice in the church. Eleanor Rigby picks upthe rice in the church. (gene duplification)Rearrangement: Gene gets transposed to another chromosome.
    21. 21. Gene duplication: A major event in evolutionGene duplications produce copy number variations (CNV) inhumans
    22. 22. Copy number variation (CNV)Copy number for amylase-1 gene is higher in populations with a starchy diet. Amylase digests starch. 50%Perry et al.,NatureGenetics2007 Gene copy number/cell
    23. 23. How different are human beings from one another? Differences in SNPs: about 10 million (~3/1000 bases) Large deletions and insertions: about 15 million basedifferences Copy number variations: can lead to very large numbers ofbase changes
    24. 24. Risk Factors for Disease A risk factor increases your risk of developing a disease or health problem. Genes“Environment” Behaviors and lifestyle (including diet) + = EnvironmentHow can you tell which is more important? Sometimes a singlegene mutation leads to disease. THE EASY CASES
    25. 25. SICKLE CELL ANEMIA An example of a single gene disease• Caused by a mutant allele h of a hemoglobin gene H.• 1/500 black Americans have the disease. (homozygous hh)• 1/10 is heterozygous (Hh) for the sickle cell gene• The mutant gene is even more common among West African Blacks.• In some parts of Africa, the fraction of individuals with this disease is 1/25• The mutant allele confers some resistance to malaria.
    26. 26. Sickel cell anemia is caused by a single base change (SNP) Fig. 11.2
    27. 27. Some other genetic disorders caused by single genesDisorder Incidence (US) SymptomsCystic fibrosis 1/2,000 Caucasians Obstructive lung disorder, 1/17,000 African Americans infections, heart failure 1/9,000 HispanicsTay-Sachs disease 1/300,000 in US Destroys nervous system at about 8 months. Rarely live past age 2. 1/3500 in Ashkenazi JewishHuntington’s disease 1/20,000 (Western countries), Gradual deteriation of nervous less freq. in Africa & Asia systemMaple syrup urine disease 1/9,000 to 1/300,000 Vomiting, seizures, mental retard., 1/176 in PA Mennonites coma. Death in 2 yearsAlpha-1-antitrypsin 1/2000 Early lung disorder (by 40 years)BRCA1 or BRCA2 breast Will discuss later along with Increased risk for breast cancer other cancer risk genescancerPhenylketonurea (PKU) Mental retardation, excretion of phenylalanineHemophilia B X-linked recessive Lack of clotting factor IX
    28. 28. Complexities in single gene diseases: Cystic FibrosisCystic fibrosis (CF) is caused by an autosomal recessive mutation inthe gene CFTR (cystic fibrosis trans-membrane conductanceregulator).However, it is not possible to predict the exact phenotype of thisdisease from analysis of CFTR mutations. Other genes modify thedisease.
    29. 29. Polygenic inheritance The Harder cases• These underlie some of the more clinically important human diseases including • Heart disease • Stroke • Diabetes • Schiozphrenia
    30. 30. Body Mass Index (BMI)• At least 17 genes interact to control body weight: Genes that affect how much we eat, metabolic rate and fat distribution.• One of these genes encodes a protein hormone called leptin. Eating stimulates fat cells to secrete leptin. Leptin travels to the brain and signals it to supress appetite and increase metabolism to digest the food.• Low levels of leptin indicate starvation, which triggers hunger and decreases the metabolic rate.• However, body weight is not entirely genetically determined.
    31. 31. Breast cancer risk differs in different countries: Heredity or Environment? US
    32. 32. Breast cancer risk cannot be entirely genetic.For example, diet, obesity, radiation exposure, and alcoholuse influence risk. e.g. Alcohol Use• Adult use associated with risk (about 10% increase for each drink per day)• All studies have reported impact of early age alcohol use on breast cancer risk• About twice the risk of breast cancer for women below 35 years• Alcohol use increases estrogen levels• Adequate folic acid (B vitamin) may decrease risk in women who have more than 1 drink per day
    33. 33. Another example: stomach cancerHigh incidence in Japanese men in Japan, but lower in Hawaii
    34. 34. Example of multifactor causation: breast cancer or
    35. 35. Other inherited cancer syndromesSyndrome Primary tumors Other tumors/traitsDominantFamilial retinoblastoma retinoblastoma osteosarcomaHered. non-polyposis colon can. colorectal manyFamilial adenomatous polyposis colorectal other GI, jaw, brainNevoid basal cell carcinoma skin jaw cysts, ovary, fibomasFamilial melanoma skin pancreasMultiple endocrine neoplasia (1/2) pancreas(1), thyroid(2) other endocrineLi-Fraumeni syndrome sarcoma, breast brain, leukemiasRecessiveAtaxia telangiectasia lymphoma cerebellar ataxiaBloom’s syndrome solid tumors immunodeficiency, small statureXeroderma pigmentosum skin abnormal pigmentationFanconi’s anemia AML skeletal abnormalities
    36. 36. Chemical carcinogens often cause DNA damage which leads to mutations if the damage is not repaired N2 H O N N OP O - A O ON N Mutation O O N H Exposure to Metabolic - OP O T O ON O mutagenic/carcinogenic activation compounds O G* O N N H - Cancer OP O O ON N NH H N2 O H HO OH O N - OP O N O O O C DNA repair O DNA adduct No Cancer
    37. 37. DNA repair defect diseases
    38. 38. Involvement of BRCA1 in DNA repairProteins known to bind to BRCA1’s BRCT domains—such as Abraxas, BACH1, and CtIP—are all involved inthe DNA repair process.This meshes with the prevailing view that faulty DNArepair by a mutated BRCA1 results in genomicinstability, which ultimately leads to tumorigenesis.
    39. 39. 2007: The Year of GWA StudiesPennisi E, Science 2007; 318:1842-43.
    40. 40. THE NEWEST METHOD FOR GENETIC ANALYSIS: Genome-Wide Association Study (GWAS)GWAS is an approach that involves rapidly scanning geneticmarkers across the complete sets of DNA (genomes), of manypeople to find genetic variations associated with a particulardisease.Such studies are being carried out to find genetic variationsthat contribute to common, complex diseases, such asasthma, cancer, diabetes, heart disease and mental illnesses.
    41. 41. The Gene Chip (microarray)
    42. 42. Microarray chipsOligonucleotide probes representing manygenes are spotted in an array.
    43. 43. Types of microarraysComparative Genomic Hybridization (CGH): for genomic gains and losses or for a change in the number of copies of a particular gene.Microarray expression analysis: to determine the level of expression of a gene. Reflects subject’s mRNA levels.SNP or mutation analysis: In this case, gene sequences placed on any given spot within the array will differ from that of other spots, by only one (SNP) or a few specific nucleotides.
    44. 44. Genome-Wide Scan for Type 2 Diabetes in a Scandinavian Cohort: SNP resultsttp://www.broad.mit.edu/diabetes/scandinavs/type2.html
    45. 45. Type 2 DiabetesGWAS have accelerated the identification of type 2diabetes susceptibility genes. There are now at least 19 locicontaining genes that increase risk of type 2 diabetes.Individually, most of these variants confer a modest risk(odds ratio [OR] = 1.1–1.25) of developing type 2 diabetes.To date, these approaches have only identified two genes:PPARG (peroxisome proliferator-activated receptor-r ) andKCNJ11(potassium inwardly-rectifying channel J11)robustly implicated in type 2 diabetes susceptibility.
    46. 46. GWAS for SNP Associations with Myocardial Infarction show hot region on Ch 9Samani N et al., N Engl J Med 2007; 357:443-53.
    47. 47. GWAS for Age-Related Macular DegenerationKlein et al, Science 2005; 308:385-389.
    48. 48. Wellcome Trust GWAS of Seven DiseasesWTCCC,Nature 2007;447:661-678.
    49. 49. BIG SURPRISE: Most SNPs associated withdisease susceptibility are in introns and intergenic positions!!
    50. 50. Unique Aspects and problems of GWAS• GWAS permits examination of inherited genetic variability at unprecedented level of resolution.• GWAS permits "agnostic" genome-wide evaluation.• Once a genome is measured, it can be related to any trait.• Most robust associations in GWA studies have not been with genes previously suspected of association with the disease.• Many associations are in regions that do not harbor genes. But with more than 500,000 comparisons per study, the potential for false positive results is unprecedented (and expensive!). Most associations are NOT robust.
    51. 51. Further Reading (and some criticisms)Taft et al., Non-coding RNAs: regulators of disease. J.Pathology 220:126-139, 2010Roberts et al., The predictive capacity of personal genomesequencing. Science Translational Medicine 201010.1126/scitranslmed.3003380 stm.sciencemag.orgIoannidis et al., A compendium of genome-wideassociations for cancer: Critical synopsis and reappraisal.J. Natl. Cancer Inst. 102:846-858, 2010Bell, Our changing view of the genomic landscape ofcancer. J. Pathology 220:231-243, 2010Vineis and Pearce, Genome-wide association studies maybe misinterpreted: genes versus heritability.Carcinogenesis 32:1295-1298, 2011
    52. 52. WebsitesCDC, Office of Genomics and Disease Preventionwww.cdc.gov/genomics/public/famhist.htm"DNA Interactive" Site from Cold Spring Harbor Labs: http://www.dnai.org/index.htmHoward Hughes Medical Institutes "Biointeractive" Sitehttp://www.hhmi.org/biointeractive/genomics/microarray.htmlLearn Genetics — Genetic Science Learning Centerhttp://learn.genetics.utah.edu/National Center for Biotechnologyhttp://www.ncbi.nlm.nih.gov/About/primer/snps.htmlhttp://hapmap.ncbi.nlm.nih.gov/Animations On How DNA Microarrays Workhttp://www.imagecyte.com/animations/array2.htmlhttp://www.bio.davidson.edu/courses/genomics/chip/chip.html
    53. 53. Some other things besides genes are important
    54. 54. Founder EffectsOccur when a population is established by a small number ofpeople. A mutation in one of the founders becomes prevelent in theresulting population.Afrikaners (S Africa) Familial hypocholesterolemia, APC, BRCA1/2, BloomsFrench Canadians HED (skin disorder), congenital adrenal hyperplasiaFinns hMLH1, diastrophic dysplasiaIcelanders BRCA2Dutch BRCA1/2, melanomaNorwegians BRCA1North Africans Allgrove syndromeSwedes BRCA1/2African Americans BRCA1Germans (Black Forest) Von Hippel-Lindau diseaseFrance (Rhone Alps) Hemophilia BSicilians Glycogen storage disease type IISouth Italians CDA-II (anemia)
    55. 55. Steps in Chemical Carcinogenesis (also radiation)
    56. 56. HAPMAPTesting all of the 10 million common SNPs in a personschromosomes would be extremely expensive. Thedevelopment of the HapMap will enable geneticists to takeadvantage of how SNPs and other genetic variants areorganized on chromosomes. Genetic variants that are neareach other tend to be inherited together. For example, all ofthe people who have an A rather than a G at a particularlocation in a chromosome can have identical geneticvariants at other SNPs in the chromosomal regionsurrounding the A. These regions of linked variants areknown as haplotypes.
    57. 57. Diseases and Traits with Published GWA Studies (n = 76, 11/17/08)• Macular Degeneration • Lipids and Lipoproteins • Syst. Lupus• Exfoliation Glaucoma • Warfarin Dosing Erythematosus • Ximelegatran Adv. Resp. • Sarcoidosis• Lung Cancer • Pulmonary Fibrosis• Prostate Cancer • Parkinson Disease • Psoriasis• Breast Cancer • Amyotrophic Lat. • HIV Viral Setpoint• Colorectal Cancer Sclerosis • Childhood Asthma• Bladder Cancer • Multiple Sclerosis• Neuroblastoma • MS Interferon-β Response • Type 1 Diabetes• Melanoma • Type 2 Diabetes• TP53 Cancer Predispos’n • Prog. Supranuclear Palsy • Diabetic Nephropathy• Chr. Lymph. Leukemia • Alzheimer’s Disease in • End-St. Renal Disease ε4+ • Obesity, BMI, Waist, IR• Inflamm. Bowel Disease • Cognitive Ability • Height• Celiac Disease • Memory • Osteoporosis• Gallstones • Hearing • Osteoarthritis• Irritable Bowel Syndrome • Restless Legs Syndrome • Male Pattern Baldness• QT Prolongation • Nicotine Dependence• Coronary Disease • Methamphetamine • F-Cell Distribution• Coronary Spasm Depend. • Fetal Hgb Levels• Atrial Fibrillation/Flutter • Neuroticism • C-Reactive Protein• Stroke • Schizophrenia • ICAM-1• Subarachnoid • Sz. Iloperidone Response • Total IgE Levels Hemorrhage • Bipolar Disorder • Uric Acid Levels, Gout• Intracranial Aneurysm • Family Chaos • Protein Levels• Hypertension • Narcolepsy • Vitamin B12 Levels• Hypt. Diuretic Response • Attention Deficit • Recombination Rate

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