HUMAN GENOME PROJECT

Dr. Aslı Tolun

Dept. of Molecular Biology and Genetics

Boğaziçi University

DNA helix

GENETICS Chemical molecule: a DNA chain 4 types of nucleotides (A, G, C, T) DNA codes for proteins Example: insulin gene

→ insulin hormone

FLOW of GENETIC INFORMATION DNA → codes for proteins

DNA: ATGGCCTTAGATCATAGG Coding: ATGGCCTTAGATCATAGG Protein aa1 aa2 aa3 aa4 aa5 aa6

GENOME:total genetic information3.3 billion nucleotides

99.9% are same in all24 chromosomes (24 DNA molecules)Human Genome Project

Total DNA sequence (=> genes)

ProteomicsFunctions of all genes (proteins)

PROTEOMICS

WHY study it: Scientific curiosity Human evolution Interaction of environment with

genetics Basis for inherited disorders

The PROJECT

1986 proposed

1990 initiated

April 2003 ‘completed’ (2005)

April 2004

Mistakes 1:100 000

Today almost complete

INTERNATIONAL COLLABORATION USA, ENGLAND, FRANCE, GERMANY,

JAPAN, CHINA:

20 research centers

PURPOSE

All of DNA sequence Sequences of all genes Functions of all genes Establishment of data bases Develeopment/improvement of techniques Ethical, legal and social issues

WHY STUDY GENOMICS?

Scientific curiosity Human evolution Interaction of genetics and environment Genetic basis of inherited diseases Prevention (genetic councelling) Developing therapeutic means

FIRST RESULTS 2003

Genes constitute about 5% of the genome Genes: < 30 000. (Earlier guess: 80 000) Half are “unknown genes” About 99.9% are same in all individuals A difference of about 3 million nucleotides

-> Susceptibilities to diseases?

MAJORITY OF OUR GENES ARE SHARED 21% – by all organisms 32% – by all eukaryotes 24% – by all animals 22% – by only vertebrates 1% – only in “humans”

SIMILARITY TO OTHER SPECIESGenes:

99% shared by mouse

(diverged 75 million years ago)

61% shared by fruit fly (Drosophila)

43% with a small nematode

(diverged 500 million years ago)

COMPARATIVE GENOMICS

Chimpanzee, gorilla, monkeys, mouse, rat, cow, dog, chicken, fish, primitive vertebrates, bee, mosquito, fruit fly, nematode, yeast, plants, bacteria etc.

UNDERSTANDING GENE FUNCTION NUCLEOTIDE SEQUENCE (domains)

SIMILARITY TO OTHER GENES

ANIMAL MODELS

GENETIC DISEASES

Balat Or-Ahayim Hastanesi 14 Mart 2010

Waardenburg Syndrome

Balat Or-Ahayim Hastanesi 14 Mart 2010

Leptin gene knock-out mouse

29 Eylül 2009 Kocaeli Üniversitesi 18

BRAIN ENLARGEMENT

1.23% difference between genes, h vs chimp Brain/body weight ratio: 3x larger in humans “Microcephaly genes” identified:

ASPM gene: very different from chimp’s MCPH1 gene: diverged early

PRACTICAL USE of HGP?

An example60% of our genes are similar to fruit fly’s

Similarly, 2/3 of our ‘cancer genes’

‘Parkinson gene’ to fruit fly disease

RESEARCH EXAMPLES

Evolution of stomach ulcer bacterium

Origin of American dog

Evolution of crops

Domestication of animals

Balat Or-Ahayim Hastanesi 14 Mart 2010

TRANSGENIC ANIMALSRat growth hormone to mouse

DISEASE GENE HUNT

BENEFITS: Scientific Families

Prevention (Genetic counseling)

Developing therapeutic interventions

FREQUENCY OF DISEASES

RECESSIVES ARE VERY FREQUENT

Carrier Patient Increase in

freq. freq. cousin marriage

1:50 1:10,000 7 x

1:1,000 1:4 million 126 x

1:50,000 1:10 billion 6251 x

Split Hand/Foot Malformation - AR

ETHICSUniversal values: Honesty / integrity Awareness of responsibilities and duties Respect for human rights and dignity Respect for others’ rights

STUDENT ETHICS NOT CHEATING in Exams Homeworks Reports

FOR THESIS WORK: Obligatory course on bioethics Learn research ethics Ethical review for research

HGP ETHICAL ISSUES

No discrimination Respect to privacy Confidentiality of data Informing the subject Informed consent form Help to cope with psycological effects Patents, ownership, etc.

Genetic studies withHUMAN PARTICIPANTS Medical applications Genetic applications Research

UNESCO Declarations and Resolutions 1948 Human Rights Universal Declaration Agreements against discrimination:

1965 Racial discrimination

1979 Discrimination against women

1989 Children’s rights

2001 Genetics and discrimination 1998 Human Genome and Human Rights

Universal Declaration

UNESCO 1997 Universal Declaration onthe Human Genome and Human Rights

Human genetic data: Obtaining Processing Use Storage

UNESCO 2005 Universal Declaration on Bioethics and Human Rights

Respect to: Human dignity Human rights Basic freedom.

ETHICAL PRINCIPLES Apply for all individuals without discrimination

Individual’s advantage should come before that of society and community

Individual’s benefit should be maximized while any potential harm is minimized.

ETHICAL COMMITTEE REVIEWS

Institutional ethical review boards

A national ethical council

OBTAINING CONSENT Without pressure, on free will Those not competent.... Children 11-18 yrs Sufficiently-informed A copy of the informed consent form The right to withdraw consent Research to be initiated after consent

PARTICIPANT’S RIGHTS To know and not to know Psychological support Access to treatment and cure

MINORS’ RIGHTS 11-18 yrs: consent Genetic testing – only if a ‘good reason’ Should the parents know the results? At what age should the result be told?

By whom?

RESPONSIBILITIES of the STATE National ethics councils

Sufficient ethics training for workers Inform relevant UNESCO committees

about whether the declarations are followed in the country.

CONTROVERCIAL ISSUES Gene therapy Sex selection in embryo (male/second) Embryo selection for histocompatibility Embryo selection for a trait (deafness) Filing of the genetic data by the state Availability of that data.

FUTURE SENARIOS Obligation for prenatal genetic testing Obligatory genetic testing for “aggressivity” Genetic classification in athletes Insurance companies’ demands Demands of the employer ‘Designer’s baby’.

KAYNAKÇAAvrupa Birliği: Avrupa’da Genetik ve Kamu ve Profesyonel Politikalarhttp://europa.eu.int/comm/research/biosociety/pdf/bmh4_ct98_0550_partb.pdfAvrupa Konseyi – Genetik testin etik, yasal ve sosyal açılımları üzerine 25

Öneri ve diğer öneriler http://ec.europa.eu/research/science-society/ABD Ulusal Sağlık Enstitüleri Sağlık ve İnsan Servisleri Araştırma

Risklerinden Koruma Ofisi http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm

Helsinki Bildirgesi, Dünya Tıp Birliği http://www.wma.net/e/policy/b3.htmİngiltere Genetik Test için Danışma Komitesi

ttp://www.doh.gov.uk/genetics/recrev3.htmNürnberg İlkeleri http://ohsr.od.nih.gov/nuremberg.php3UNESCO uluslararası bildirgeler www.unesco.orgİnsan Hakları Taraftarı Tüm Avukat ve Hekimler http://www.glphr.orgABD Başkanlık Biyoetik Kurulu http://www.bioethics.govİngiltere İnsan Genetiği Komisyonu http://hgc.gov.ukGenetik Araştırma ve Uygulamada Etik. TÜBA Yayınları

http://www.tuba.gov.tr/