1.2 Cell Division

8/6/2019 1.2 Cell Division

1/92


2/92


3/92

INTRODUCTION

The cells composing the body continue todivide throughout life. Cell division ensures

sustenance and propagation of life. As thecells grow, they reproduce themselves, wherea diploid cell splits to produce new diploids,each of which is a replica of the original.

Without cell division, an organisms cellswould not regenerate, resulting in not only celldeath but also the death of the entire organism.


4/92

Cell division

Cell division is aprocess by which acell called the parentcell, divides into twoor more cells, calleddaughter cells . Celldivision is usually asmall segment of alarger cell cycle.


5/92

PHASES OF C ELL CYC LE

Interphase: G1, S and G2Cell Division: M


6/92


7/92

M ITO SIS

Mitosis is the process inwhich a cell separates thechromosomes in its cellnucleus, into two identical

sets. It is generally followedimmediately by cytokinesis,which divides the nuclei,cytoplasm, organelles and

cell membrane into twodaughter cells. Mitosis andcytokinesis together definethe mitotic (M) phase of thecell cycle.


8/92

F EA TUR ES

It occurs only in somatic cells.

It ensures sustenance of life.

The daughter cells carry same

number of chromosomes as parent

cell.


9/92

PHASES

M itosis

P rophase M etaphase Anaphase Telophase


10/92

P rophase

At the beginning of the prophase, thechromosomes become contracted andthus much thicker and can be fixed andstained. While entering in prophasechromosomes have already splitlongitudinally into two chromatids, but

they remain attached to each other at thecentromere.


11/92

M etaphase

The nuclear membrane disappears andchromosomes become oriented in the centreof the nucleus. The spindle formation occurs

at this time. This structure is responsible for the movement of chromosomes to theopposing poles of the cell. The centrosomedivides into two and moves to the opposite

poles of the nucleus and remains inconnection with the spindle.


12/92

Anaphase

The onset of this phase is marked bydivision of centromere into two of each

chromosome. This divided centromerethen repels each other, so that the twochromatids are dragged apart inopposite direction towards the pole of the spindle.


13/92

Telophase

The daughter chromosomes(chromatids) have separated completely

and the nuclear membrane nowreappears enclosing the two groups of daughter chromosomes withcytoplasmic division over, the two newcells are formed and they enter intointerphase.


14/92


15/92

S ignificance

The importance of mitosis is the maintenanceof the chromosomal set; each cell formedreceives chromosomes that are alike incomposition and equal in number to thechromosomes of the parent cell. Transcriptionis generally believed to cease during mitosis,but epigenetic mechanisms such asbookmarking function during this stage of thecell cycle to ensure that the "memory" of which genes were active prior to entry intomitosis are transmitted to the daughter cells.


16/92

Consequences of errors

Although errors in mitosis are rare, theprocess may go wrong, especially

during early cellular divisions in thezygote. Mitotic errors can be especiallydangerous to the organism becausefuture offspring from this parent cellwill carry the same disorder.


17/92

In non- disju n cti on , a chromosome may fail toseparate during anaphase. One daughter cellwill receive both sister chromosomes and theother will receive none. This results in the

former cell having three chromosomes codingfor the same thing a condition known astris omy , and the latter cell having only onechromosome (the homologous chromosome),

a condition known as mono s omy .


18/92

Mitosis is a traumatic process. The cell goesthrough dramatic changes in ultra structure, its

organelles disintegrateOccasionally, chromosomes may become damaged.An arm of the chromosome may be broken and thefragment lost, causing deletion.

The fragment may incorrectly reattach to another,non-homologous chromosome, causingtranslocation.It may reattach to the original chromosome, but in

reverse orientation, causing inversion.It may be treated erroneously as a separate

chromosome, causing chromosomal duplication.


19/92

M E IO SIS

Meiosis is a process of reductionaldivision in which the number of

chromosomes per cell is cut in half. Inanimals, meiosis always results in theformation of gametes, while in other

organisms it can give rise to spores.


20/92

F EA TUR ES

It occurs only in germ cells.It is a reduction division (chromosomeshalved from 46 to 23).It includes two successive divisions(Meiosis 1 and Meiosis 2).

Meiosis determines inheritance and

ensures propagation of species.


21/92

P ROC ESS

Meiosis is the process of nuclear division,which occurs when the gametes are formed.Meiosis takes place in two steps, each of which

has a prophase, metaphase, anaphase andtelophase stages as in mitosis. The preparatorysteps that lead up to meiosis are identical inpattern and name to the interphase of the

mitotic cell cycle. Interphase is followed bymeiosis 1 and then meiosis 2.


22/92

Interphase

Gap 1(G1) : This is a very active period, wherethe cell synthesizes its vast array of proteins,including the enzymes and structural proteins

it will need for growth. In G1 stage, each of thechromosomes consists of a single (very long)molecule of DNA. In humans, at this point cellsare 46 chromosomes, 2N, identical to somatic

cells.


23/92

Synthesis (S) phase: The genetic material isreplicated: each of its chromosomesduplicates, producing 46 chromosomeseach made up of two sister chromatids. The

cell is still considered diploid because it stillcontains the same number of centromeres.

Gap 2 (G2) phase: G2 phase is absent inMeiosis


24/92

M eiosis-phaseIn meiosis I, the homologous pairs in a diploid cellseparate, producing two haploid cells (23chromosomes, N in humans), so meiosis I isreferred to as a reductional division. A regular

diploid human cell contains 46 chromosomes andis considered 2N because it contains 23 pairs of homologous chromosomes.In meiosis II , an equational division similar to

mitosis will occur whereby the sister chromatidsare finally split, creating a total of 4 haploid cells(23 chromosomes, N) per daughter cell from thefirst division.


25/92

P rophase I

Homologous chromosomes pair (or synapse)and crossing over (or recombination) occurs - astep unique to meiosis. The paired andreplicated chromosomes are called bivalents or tetrads, which have two chromosomes and four chromatids, with one chromosome coming

from each parent.


26/92

Leptotene : The first stage of prophase I is the

lept o te n e stage, also known as lept on e m a ,from Greek words meaning "thin threads.During this stage, individual chromosomesbegin to condense into long strands within the

nucleus. Zygotene :The z y g o te n e stage, also known as

z y g on e m a , from Greek words meaning "pairedthreads,"occurs as the chromosomes

approximately line up with each other intohomologous chromosomes.


27/92

Diplotene

During the dipl o te n e stage, also known as dipl on e m a ,from Greek words meaning "two threads, thehomologous chromosomes separate from one another a

little. The chromosomes themselves uncoil a bit,allowing some transcription of DNA. However, thehomologous chromosomes of each bivalent remaintightly bound, the regions where crossing-over occurred.


28/92

DiakinesisChromosomes condense further during thediaki n esis stage, from Greek words meaning,"Moving through." This is the first point in meiosiswhere the four parts of the tetrads are actuallyvisible. Sites of crossing over entangle together,effectively overlapping, making chiasmata clearlyvisible. Other than this observation, the rest of thestage closely resembles prometaphase of mitosis;

the nucleoli disappear, the nuclear membranedisintegrates into vesicles, and the meiotic spindlebegins to form.


29/92

Synchronous processes

During these stages, two centrosomes, containing a pair of centrioles in animal cells, migrate to the two poles of the cell. These centrosomes, which were duplicatedduring S-phase, function as microtubule organizingcenters nucleating microtubules, which are essentiallycellular ropes and poles. The microtubules invade thenuclear region after the nuclear envelope disintegrates,attaching to the chromosomes a the kinetochore. Thekinetochore functions as a motor, pulling thechromosome along the attached microtubule toward theoriginating centriole, like a train on a track. There arefour kinetochores on each tetrad, but the pair of kinetochores on each sister chromatid fuses andfunctions as a unit during meiosis I.


30/92

M etaphase IHomologous pairs move together along themetaphase plate: As kinetochore microtubulesfrom both centrioles attach to their respectivekinetochores, the homologous chromosomes alignalong an equatorial plane that bisects the spindle,due to continuous counterbalancing forces exertedon the bivalents by the

microtubules emanating

from the two kinetochores

of homologous

chromosomes.


31/92

Anaphase IK inetochore microtubules shorten, severing therecombination nodules and pulling homologouschromosomes apart. Since each chromosome has onlyone functional unit of a pair of kinetochores, wholechromosomes are pulled toward opposing poles,

forming two haploid sets. Each chromosome stillcontains a pair of sister chromatids. Nonkinetochoremicrotubules lengthen, pushing the centrioles farther apart. The cell elongates in preparation for divisiondown the center.


32/92

Telophase I

The last meiotic division effectively ends when thechromosomes arrive at the poles. Each daughter cellnow has half the number of chromosomes but eachchromosome consists of a pair of chromatids. Themicrotubules that make up the spindle networkdisappear, and a new nuclear membrane surroundseach haploid set. The chromosomes uncoil back intochromatin. Cytokinesis, the pinching of the cell

membrane in animal cells or the formation of the cellwall in plant cells, occurs, completing the creation of two daughter cells. Sister chromatids remain attachedduring telophase I.


33/92

M eiosis II

Meiosis II is the second part of the meioticprocess. Much of the process is similar to

mitosis. The end result is production of four haploid cells (23 chromosomes, 1N in humans)from the two haploid cells (23 chromosomes,1N * each of the chromosomes consisting of

two sister chromatids) produced in meiosis I.


34/92

P rophase II takes an inversely proportional timecompared to telophase I. In this prophase we seethe disappearance of the nucleoli and the nuclear envelop again as well as the shortening andthickening of the chromatids. Centrioles move to

the polar regions and arrange spindle fibers for thesecond meiotic division.In metaphase II , the centromeres contain twokinetochores, that attach to spindle fibers from the

centrosomes (centrioles) at each pole. The newequatorial metaphase plate is rotated by 90degrees when compared to meiosis I,perpendicular to the previous plate.


35/92

This is followed by anaphase II , where thecentromeres are cleaved, allowing microtubulesattached to the kinetochores to pull the sister chromatids apart. The sister chromatids byconvention are now called sister chromosomes asthey move toward opposing poles.

The process ends with telophase II , which issimilar to telophase I, and is marked by uncoilingand lengthening of the chromosomes and thedisappearance of the spindle. Nuclear envelopes

reform and cleavage or cell wall formationeventually produces a total of four daughter cells,each with a haploid set of chromosomes. Meiosisis now complete.


36/92

S ignificance of M eiosisMeiosis facilitates stable sexual reproduction. Withoutthe halving of ploidy, or chromosome count, fertilizationwould result in zygotes that have twice the number of chromosomes as the zygotes from the previousgeneration.P lants, however, regularly produce fertile, viablepolyploids. P olyploidy has been implicated as animportant mechanism in plant speciation.

Most importantly, recombination and independent

assortment of homologous chromosomes allow for agreater diversity of genotypes in the population. Thisproduces genetic variation in gametes that promotegenetic and phenotypic variation in a population of offspring.


37/92


38/92

Introduction

The law of inheritance were derived by

Gregore Mendel, a 19th century Monkconducting hybridization experiments ingarden peas. From these experiments hededucted two generalizations which later

became known as Mendles laws of heredityor Mendelian Inheritance.


39/92

Cont.Mendelian inheritance (or Mendeliangenetics or Mendelism) is a set of primarytenets relating to the transmission of

hereditary characteristics from parentorganisms to their children; it underliesmuch of genetics. They were initiallyderived from the work of Gregor Mendel

published in 1865 and 1866 which was"re-discovered" in 1900.


40/92

M endel's L awsThe principles of heredity were written by Gregor Mendelin 1865. Mendel discovered that by crossing white flower and purple flower plants, the result was a hybridoffspring.

He then conceived the idea of heredity units, which hecalled "factors", factors, later called genes, one which isa recessive characteristic and the other dominant.Thedominant gene, such as the purple flower in Mendel'splants, will hide the recessive gene, the white flower.

After Mendel self-fertilized the F1 generation andobtained the 3:1 ratio, he correctly theorized that genescan be paired in three different ways for each trait; AA,aa, and Aa. The capital A represents the dominant factor and lowercases a represent the recessive.


41/92

ContMendel stated that each individual has two factors for each trait, one from each parent. The two factors mayor may not contain the same information. If the twofactors are identical the individual is calledhomozygous for the trait. If the two factors have

different information, the individual is calledheterozygous.

The alternative forms of a factor are called alleles. Thegenotype of an individual is made up of the manyalleles it possesses. An individual's physicalappearance, or phenotype, is determined by its allelesas well as by its environment.


42/92

ContAn individual possesses two alleles for each trait; oneallele is given by the female parent and the other by themale parent. They are passed on when an individualmatures and produces gametes, egg and sperm. Whengametes form the paired alleles separate randomly so

that each gamete receives a copy of one of the twoalleles.

The presence of an allele doesn't promise that the traitwill be expressed in the individual that possesses it. Inheterozygous individuals the only allele that inexpressed is the dominant. The recessive allele ispresent but its expression is hidden.


43/92

M endels FindingsL aw of SegregationThe L aw of Segregation states that when anyindividual produces gametes, the copies of a geneseparate, so that each gamete receives only one

copy. A gamete will receive one allele or the other.In meiosis the paternal and maternal chromosomes

get separated and the alleles

with the characters are

segregated into two differentgametes.


44/92

L aw of Independent Assortment

The L aw of Independent Assortment, alsoknown as " Inheritance L aw", states that allelesof different genes assort independently of oneanother during gamete formation.

Mendel's experiments with mixing one traitalways resulted in a 3:1 ratio

between dominant and

recessive phenotypes, his

experiments with mixing

two traits showed

9:3:3:1 ratios.


45/92

The 9:3:3:1shows that each of the two genesare independently inherited with a 3:1 ratio.

Mendel concluded that different traits are

inherited independently of each other, so thatthere is no relation, for example, between acat's color and tail length. This is actuallyonly true for genes that are not linked to each

other.


46/92

ContIndependent assortment occurs during meiosis I ineukaryotic organisms, specifically anaphase I of m ei o sis , to produce a gamete with a mixture of theorganism's maternal and paternal chromosomes.

The 46 chromosomes in a normal diploid humancell, half are maternally-derived and half arepaternally-derived.

During gametogenesis - the production of newgametes by an adult - the normal complement of 46chromosomes needs to be halved to 23 to ensurethat the resulting haploid gamete can join withanother gamete to produce a diploid organism.


47/92


48/92

INTRODUCTIONThe idea of mutation first originated fromobservations of a Hugo de Vries(1880s)on variations in plants. He found that

heritable variations were distinct fromenvironmental variations. He gave thename mutation to heritable changes. In1901 published a book entitled TheMutation Theory. Although De Vries iscredited with the discovery of the idea of mutations.


49/92

M UT ATION

A mutation occurs when a DNA gene is damaged or changed in such a way as to alter the genetic messagecarried by that gene.

A mutation is a permanent change in the DNA sequenceof a gene. Mutation is a genes DNA sequence can alter the amino acid sequence of the protein encoded by thegene.

L ike words in sentence, the DNA sequence of each

gene determines the amino acid sequence for theprotein it encodes. The DNA sequence is interpreted ingroups of three nucleotide bases, called condos. EachCondon specifies a single amino acid in a protein.


50/92

The DNA sequence of a gene as a sentence made up entirelyof three letter words. In the sentence, each three letter word isa Condon, specifying a single amino acid in a protein.E g: Thesunwashotbuttheoldmandidnotgetthishot.If you were split this sentence into there letter words, itbecomes

* The sun was hot but the old man did not get this hot.If you shifted the three letter reading frame, it becomes

* T hes unw ash otb uttbheo ldm and idn olg eth ish at. OR

* Th esu sho tbu tth eol dma ndi dno tge this ha t.

As only one of these three reading frames translate into

understandable sentence. In the same way, only one threeletter reading frame within a gene codes for the correctprotein.


51/92

The early concepts of mutation therefore aroseout of genetic studies of visible phenotypes.

L ater by the middle of the twentieth century, the

molecular basis of heredity began to beinvestigated. It became established that thetransmission of hereditary traits takes placedue to an accurate process of self replication of the genetic material DNA.


52/92

W AYS OF MUT A T IONINHER ITED: Mutations that are passed from parent tochild are called hereditary or germline mutation. Thistype of mutation is present throughout a persons life invirtually every cell in the body.

ACQU IRED: Mutation occur in the DNA of individualcells at some time during a persons life. These changescan be caused by environment factors such asultraviolet radiation from the sun or can occur if a

mistake is made as DNA copies itself during celldivision. These mutations can be passed on to the nextgeneration.


53/92

TY PES OF M UT ATION S

Single base substitutions

Insertions and deletions

Chromosomal mutations


54/92

Single base substitutions

A single nucleotide base is replaced. Thesesingle base changes are also called pointmutations. If a purine (a, t) replaces a purine or a pyrimidine (c, g) replaces a pyrimidine, it iscalled a transition. If a purine replaces apyrimidine or vice-versa, the substitution iscalled a transversion.


55/92

1. Missense mutationsIn a missense mutation, the new base alters a

condon resulting in a different amino acid beingincorporated into the protein chain. This is whathappens in sickle cell anaemia. The 17th nucleotide of the gene for the beta chain of haemoglobin is changedfrom an 'a' to a 't'. This changes the codon from 'gag' to'ggt' resulting in the 6th amino acid of the chain beingchanged from glutamic acid to valine. This apparentlytrivial alteration to the beta globin gene alters thequaternary structure of haemoglobin, which has aprofound influence on the physiology and wellbeing of the individual.


56/92

2. N onsense mutationsIn a nonsense mutation, the new base

changes a codon that specified an amino acidinto one of the stop codons (taa, tag, tga). Thiswill cause translation of the mRNA to stopprematurely and a truncated protein to be

produced. This truncated protein will beunlikely to function correctly. Nonsensemutations occur in between 15% to 30% of allinherited diseases including cystic fibrosis,

haemophilia, retinitis.


57/92

3. Silent mutations

Silent mutations are those that cause nochange in the final protein product and can only bedetected by sequencing the gene. Most amino acidsthat make up a protein are encoded by severaldifferent codons. So, if for example, the third basein the 'cag' codon is changed to an 'a' to give 'caa',a glutamine (Q) would still be incorporated into theprotein product, because the mutated codon stillcodes for the same amino acid. These types of mutations are 'silent' and have no detrimentaleffect.


58/92

Insertion and Deletion

Extra base pairs may be added or deleted fromthe DNA of a gene. The number of bases canrange from a few to thousands. Insertions anddeletions of one or two bases or multiples of one or two cause frameshifts (shift the readingframe). These can have devastating effectsbecause the mRNA is translated in new groupsof three nucleotides and the protein beingproduced may be useless.


59/92


60/92

Chromosomal M utation

A chromosome mutation is any change in thestructure or arrangement of the chromosomes.Mutations to chromosomes happen mostfrequently meiosis. There are many different

types of mutation that can change thechromosome structure resulting in changes tothe genotype and phenotype of the organism.Chromosomal mutations effecting essential

parts of the DNA can result in the abortion of thefetus before birth.


61/92

Translocationsy

Translocations are the transfer of a piece of one chromosome to anon-homologous chromosome.They are often reciprocal, with thetwo chromosomes swappingsegments with each other. Anabnormal hybrid gene is createdleading to the production of anovel protein that is not normally

found in the cell. This proteinprevents normal growth anddevelopment, leading toleukaemia.


62/92

Deletions - A large sectionof a chromosome can be

deleted resulting in theloss of a number of genes.

Duplications - In thismutation, some genes areduplicated and displayedtwice on the samechromosome.


63/92

y Chromosome non-disjunction - During

cell division, the chromosomes fail tosuccessfully separate to opposite poles,resulting in one of the daughter cells havingan extra chromosome and the other

daughter cell lacking one.y If this non-disjunction occurs in

chromosome 21 of a human egg cell, acondition called Downs syndrome (DS)

occurs. A person suffering with DS has 47chromosomes in every cell instead of thenormal 46.


64/92

Causes of M utations

DNA fails to copy accuratelyMost of the mutations that we thinkmatter to evolution are "naturally-

occurring." For example, when a celldivides, it makes a copy of its DNA and sometimes the copy is not quiteperfect. That small difference fromthe original DNA sequence is amutation.


65/92

External influences can create mutations

Mutations can also be caused by exposure tospecific chemicals or radiation. These agentscause the DNA to break down. Nevertheless,when the cell repairs the DNA, it might not do aperfect job of the repair. So the cell would endup with DNA slightly different than the originalDNA and hence, a mutation.


66/92


67/92

INTRODUCTION

The human genome project was an internationalresearch effort to determine the sequence of thehuman genome and identify the genes that itcontains. The project was coordinated by the

national institutes of health and the USdepartment of energy. Additional contributorsincluded universities across the United States andinternational partners in the United K ingdom,

France, Germany, Japan, China andIndia. Thehuman genome project formally began in 1990

and was completed in 2003, 2 years ahead of itsoriginal schedule.


68/92

ContThe work of the human genome project has allowed

researchers to begin to understand the blueprint for building a person. As researcher learn about more thefunctions of genes and proteins, this knowledge will have amajor impact in the fields of medicine, biotechnology andthe life sciences.

The Human Genome P roject, one of the most significantresearch of the twentieth century deserves much of thecredit for the discovery of these new applications of geneticinformation. Especially research from the HG P is providing

a new and better understanding of the genetic contributionto disease, the development of targeted drug therapy andthe development of genetic tests that identify those whomay have or are at risk for genetic disease.


69/92

G O ALS OF H G P

The main goals of the human genome project were toprovide a complete and accurate sequence of the 3 billionDNA base pairs that make up the human genome and tofind all of the estimated 20,000 to 25,000 human genes.

The project also aimed to sequence the genomes of several

other organisms that are important to medical research,such as the mouse and the fruit fly.In addition to sequencing DNA, the human genome projectsought to develop new tools to obtain and analyze the dataand to make this information widely available.

The human genome project committed to exploring theconsequences of genomic research through its ethical,legal, and social implications (E L S I) program.


70/92

ACCO M PL ISH M E NT S OF H G P

In April 2003, researchers announced that thehuman genome project had completed a high-quality sequence of essentially the entirehuman genome. This sequence closed the gaps

from a working draft of the genome, which haspublished in 2001. It also identified thelocations of many human genes and providedinformation about their structure and

organization. The project made the sequence of the human genome and tools to analyze thedata freely available via the internet.


71/92

ContIn addition to the human genome, the HumanGenome P roject sequenced the genomes of

several other organisms, including yeast, theroundworm, and the fly.

In 2002, researchers announced that they hadalso completed a working draft of the mousegenome.

By studying the similarities and differences

between human genes and those of other organisms, researchers can discover thefunctions of particular genes and identifywhich genes are critical for life.


72/92

E T H IC AL, LE G AL AND SOCI AL IM PL IC ATION S OF H G P

The ethical, legal and social implications (E L S I)program was founded in 1990 as an integral partof the Human Genome P roject. The mission of the E L S I program was to identify and addressissues raised by genomic research that wouldaffect individuals, families, and society. Apercentage of the Human Genome P rojectbudget at the National Institute of Health andthe US Department of Energy was devoted toEL S I research.

Th ELS I f d h ibl


73/92

The ELS I program focused on the possibleconsequences of genomic research in four main areas

P rivacy and fairness in the use of geneticinformation, including the potential for geneticdiscrimination in employment and insurance.

The integration of new genetic technologies, suchas genetic testing, into the practice of clinicalmedicine.

Ethical issues surrounding the design and conductof genetic research with people, including theprocess of informed consent.

The education of healthcare professionals, policymakers, students and the public about genetics andthe complex issues that result from genomicresearch.


74/92

FUTUR E P R ESPE CTIV E OFG E NO M IC R ESEA RC H

Discovering the sequence of the humangenome was only the first step in understandinghow the instructions coded in DNA lead to afunctioning human being. The next stage of genomic research will begin to drive meaningfulknowledge from the DNA sequence researchstudies that build on the work of the humangenome project are under way worldwide.


75/92

Objectives of Continued G enomicResearch

Determine the function of genes and the elements thatregulate genes throughout the genome.

Find variations in the DNA sequence among people and

determine their significance. These variations may oneday provide information about persons disease risk andresponse to certain medications.

Discover the 3 dimensional structures of proteins andidentify their functions.

Explore how DNA and proteins interact with one another and with the environment to create complex livingsystems.


76/92

Cont

Develop and apply genome based strategies for theearly detections, diagnosis and treatment of disease.

Sequence the genomes of other organisms, suchas the rat, cow and chimpanzee, in order tocompare similar genes between species.

Develop new technologies to study genes and DNAon a large scale and store genomic data efficiently.

Continue to explore the ethical, legal and socialissues raised by genomic research.


77/92

F i n all y , human genome project research will helpsolve one of the greatest mysteries of life how doesone fertilized egg know to give rise to so manydifferent specialized cells, such as those making upmuscles, brain, heart, eyes skin, blood and so on?For a human being or any organism to developnormally, a specific gene or set of genes must beswitched on the right place in the body at exactlythe right movement in development. Informationgenerated by the human genome project will shed

light on how this intimate dance of gene activity ischoreographed into the wide variety of organs andtissues that make up a human being.


78/92


79/92

Introduction

The series has focused on the ways in which therapidly appearing tools of genomics have alreadybegun to change the practice of medicine. In thisissue, Burke explores how genomics has startedto improve our understanding of the biology of health and disease in ways that was never beforepossible. Although the series demonstrates thatgenomics has indeed begun to change thepractice of medicine, it catalogues only the birth

of the genomic era and thus no more captures indetail the ultimate effect of genomic medicine.


80/92

OriginIf the genomic era can be said to have a precise birth

date, it was in the midst of the appearance of theseries, on April 14, 2003.

That was when the international effort known as theHuman Genome P roject put a close to the pregenomicera with its announcement that it had achieved thelast of the project's original goals, the completesequencing of the human genome.

The extent and pace of progress in genomics aresuggested by the fact that this achievement occurred

11 days shy of the 50th anniversary of the publicationof Watson and Crick's seminal description of the DNAdouble helix.


81/92

If science, technology, and medicine haveconsistently demonstrated anything, it is thatthey proceed at an ever-quickening pace. Thatwe have gone in the past 50 years from thefirst description of the structure of our DNA toits complete sequencing gives someindication of how much the impact of genomicmedicine on the health care of today'sneonates will increase by the time they turn 50years of age.


82/92

However, it is not solely the next 50 yearsthat will witness important advances ingenomic medicine. Many such advanceshave already occurred, including someduring the interval since the launch of theGenomic Medicine series.


83/92

U sesThe use of genomics for the rapid identification of newlydiscovered pathogens such as that involved in thesevere acute respiratory syndrome (SARS), the use of gene-expression profiling to assess prognosis and guidetherapy, as in breast cancer.

The use of genotyping to stratify patients according tothe risk of a disease, such as the long-QT syndrome or myocardial infarction, the use of genotyping to shed lighton the response to certain drugs, such as antiepilepticagents.

The use of genomic approaches in the design andimplementation of new drug therapies, and to improveour understanding of the role of specific genes in thecausation of common conditions, such as obesity.


84/92

During this same brief period, other notablegenomics-based advances in our understanding of biology and of health have

included the first comprehensive analysis of human chromosome 7, clarification of the male-specific region of the human Y chromosome,and the identification of the gene responsibility.


85/92

In recent months we have seen not only thepromise of the genomic era with respect to

medicine, but also its pitfalls. An example of the latter has been the revelation that

confusion and misinformation haveoccasionally accompanied the counseling of persons who undergo screening for mutations in the cystic fibrosis

transmembrane conductance regulator gene(CFTR ) the gene responsible for cysticfibrosis.


86/92

Genomics provides powerful means of discovering hereditary factors in disease. Buteven in the genomic era, it is not genes alone butthe interplay of genetic and environmentalfactors that determines phenotype (i.e., health or

disease). This point is not new, but it bearsrepeating. For example, a mutation in CHE1 maybe innocuous until a person carrying it isexposed to succinylcholine chloride anesthesia,

when it leads to prolonged apnea


87/92

Recent reports further expand our knowledge of

the complex interactions between genes and theenvironment. For instance, one such studysuggests that common variations in the serotonin-transporter gene influence the likelihood of depression after exposure to stress. Since itremains difficult to alter genes in human for thenext couple of decades we will generally usepersonalized modifications of the environment, andnot of genes, to translate genomics-based

knowledge into improvements in health for most of our patients.


88/92

With the end of the pregenomic era in sight, more

than 600 experts recently collaborated to producea vision for the future of genomic research and itsapplications to biology, health, and society.

According to that vision, within a decade or two, itwill be possible to sequence anyone's entiregenome for a laboratory cost of less than $1,000.If this proves true, one can imagine how not onlyresearch, but also clinical care, may changedramatically.


89/92

With particular relevance in the United States, is theunderstandable concern of many patients that obtaining

genetic information important to their health care is not worththe risk of discrimination stemming from the use of suchinformation by potential insurers or employers.

Although more than 40 states limit employers' and insurers'access to or use of genetic information, many people believe

that only the passage of legislation mandating uniformnational protection against the misuse of such informationwill lead to full use of genetic testing.

Congressional leaders from both major parties and thecurrent administration have supported such federallegislation, and passage of such legislation is currently closer to reality than ever before. However, until it is enacted andsigned into law, the fear of discrimination will remain.


90/92

Other social issues require our attention if genomic medicine is to benefit our patients. Howshould genetic tests be regulated? What, if any,are the appropriate uses of direct-to-consumer marketing of genetic tests? The Internet hasrecently had a proliferation of genetic-testingsites that feature claims grounded in greed andpseudoscience, rather than in data or reality. Howwill health care providers and the public

distinguish between these and responsibletesting services, whether they are availablethrough the Internet or in the hospital?


91/92

It would be easy to assume that for theforeseeable future the benefits of genomicmedicine will accrue only to people indeveloped countries. However, even in

resource-poor regions of the world, genomicapproaches can offer dramatic benefits tohealth, as the publication within the past year of the genomes for P las mo diu m f alciparu .


92/92

While recognizing such challenges, we lookforward with curiosity and real hope to theadvances of the next 50 years the first 50

years of the genomic era. As evidenced by theGenomic Medicine series, today's researchersand clinicians have already started to use thepower of genomics to improve health, and we

anticipate that this is but a hint of the progressto come.

Documents

1.2 Cell Division