WHATI

SMEDI
CALGENETI
CS?

Medi cal geneticsi nvol

vesanyappl icat
ionofgenet icstomedi calpract
ice.
I
tthusi ncludes:
 studi esoft heinheri
¬tanceofdi seasesi nfami l
i
es
 t hemappi ngofdi seasegenest ospeci ficlocationsonchr omosomes,
 anal y sesoft hemol ecularmechani smst hr
oughwhi chgenescausedi sease,
t hedi agnosi sandt r
eatmentofgenet icdis¬ease.Asar esultofrapi
dpr ogressin
mol eculargenet i
cs,genetherapy —theinsertionofnor malgenesi nt
opa¬t ientsi
n
or dert ocor rectgeneticdiseases—hasr ecentlybeeniniti
ated.
Genet iccounsel ing,
whi chinvolv
est hecommuni cati
onofin¬f or
mat i
onr egardi
ng
r
isks, prognoses, andtreatmentt opatientsandt heirf
amili
es.

TYPESOFGENETI CDI SEASES

Eachhumani sest i
mat edt ohav eapproximat ely50,000to100, 000di fferent
genes.Al t
erationsint hesegenesori ncombi nat ionsoft hem, canpr oducegenet i
c
disor ¬der s.Thesedi sor dersar eclassif
iedi nt
osev eralmajorgr oups:
1.Chr omosomedi sorder s,inwhi chentir
echr omo¬somes, orl ar
gesegment sof
them, aremi ssing,du¬pl i
cat ed,orotherwiseal tered.Thesedi sordersi n¬clude
diseasessuchasDownsy ndromeandTur nersy ndr ome.
2.Di sor dersi nwhichsi ngl egenesar ealt
ered( oftent er
med" mendel ian"condi ti
ons,
orsi ngle- genedi s¬order s).Wel l
-knownexampl esi ncludecy sticfi
brosi s,sicklecell
disease, andhemophi l
ia.
3.Mul tifactorialdi
sor ders, whichar eduet oacombi ¬nati
onofmul t
iplegenet i
cas
wel lasenv ironment alcauses.Manybi rthdef ects, suchasdef tli
pand/ ordef tpalat
e,
aswel lasmanyadul tdisor ders,i
ncludinghear tdiseaseanddi abetes, belongi nthis
cat egor y.
4.Mi tochondr i
aldisorder s, arel
at i
vel
ysmal l
numberofdi seasescausedby
alterat i
onsi nt hesmal lcy toplasmi cmitochondr i
al chromosome.

Typeofgenet i
cdi sease Li
fet
imepr
eval
enceper1,
000
Autosomal Domi nant 3to9.5
Autosomal Recessive 2to2.5
X-
linked 0.
5to2
Chromosomedi sorders 6to9
Congenital
mal f
or mati
on 20to50
TOTAL 31.
5to73

Congeni
tal
meanspr
esentatbi
rt
h
Mostcongeni
tal
malf
orma¬ti
onsaret
houghtt
obemul
ti
fact
ori
alandt
husl
i
kel
y
havebot
hgeneandenvi
ronment
alcomponent
s.
Anat omyofhumangenome
Somat iccellshav ediploidnumberofchr omosomes(hav ing23pairs
chromosomes - 22pai rsofaut osomesandoneofsexchr omosomes- ).
Gamet eshav ehapl oidnumberofchr omosomes( haveat ot
alof23
chromosomes) .
Genes, thebasi cunitofinher it
ance,arecont ainedi nchr omosomesand
consi stofDNAI tisatightlycoi l
edstructure.Thiscoi li
ngoc¬cur satseveral
l
ev els: t
henucl eosome, thesol enoid,and100- kbloops.
Thebasi cstructureofDNAi s:sugar+phosphat e+ni t
rogenousbase
(neucl eotide)
Themosti mpor t
antconst ituentofDNAi st hef ournucleot i
debases:adenine,
guani ne( purines)thymi ne,andcy t
osine(py ri
mi dines).DNAhasadoubl eheli
x
structure.
 Sequenceofeach3nucl eot i
des---
---
Codon
 Sequenceofcodons- -
--
---
Gene(f unctional entityofinformat i
on)
 Sequenceofgenes- ---
---
--Genome( humangenet icprogr am)

Ascel
lsdivi
detomakecopi esoft hemselves,i
dent i
calcopiesofDNAmust
bemadeandi ncorpor
atedintothenewcel l
s.
DNArepli
cati
onconsist
sbasi ¬call
yofthebreakingoft heweakhy drogen
bondsbe¬tweenthebases,leavi
ngasi ngl
eDNAst randwi theachbaseunpaired.
Theconsist
entpair
ingofadeni newitht
hymi neandguani newit
hcy t
osine,
knownascompl e¬mentarybasepai ri
ng,i
sthekeyt oaccur aterepl
icat
ion.
Thepri
ncipl
eofcompl ementar ybasepair
ingdictatesthattheunpairedbase
wil
latt
ractafreenucl
eoti
deonlyi
fthenucleoti
dehast hepr
opercompl
ement ary
base.Thus,aporti
onofasingl
estrandwit
ht hebasesequenceATTGCTwi l
l
bondwithaser i
esoffr
eenucleot
ideswit
ht hebasesTAACGA.
Thesinglestr
andissaidtobeat empl
ateuponwhi chacomplement
ary
str
andisbuilt
.
Whenr epli
cati
oniscomplet
e,anewdoubl e-
str
andedmoleculei
dent
ical
tot he

original i
sf or medasshowni nt hepi cturebelow.
Sev eral differentenzymesar einv olv edinDNAr epl
i¬cation.Oneenzy me
unwi ndst hedoubl eheli
x,onehol dst hest randsapart,andot hersper f
orm other
dis¬tinctf unct ions.
DNApol y mer aseisoneoft hekeyr epli
cati
onenzymes.I tt r
avelsalongt he
si
ngl eDNAst rand,addingfreenucl eot idestothe3'endoft henewst r
and.(3'
and5' referredt ono.ofthecarbonat om i nthepentosesugart owhi chthebase
i
sat tached) .
Nucl eotidescanbeaddedonl yt ot hisendofthest rand,sor epli
cationalways
proceedsf rom t he5'tothe3'end.Whenr efer
ri
ngtot heorientationof
sequencesal ongagene, t
he5' directioni ster
med" upstream, "whilethe3'
directioni st ermed" downst r
eam. "
 DNARepl icat ioni scr iti
cal lydependentont hepr i
nci pleofcompl ement arybase
pai r
ing.Thi sal ¬lowsasi ngl est randoft hedoubl e-st randedDNAmol ecul et of orm
at empl at ef ort hesy nthesi sofanew, compl ement ar yst rand.
DNAsequencesencodepr oteinst hr ought hepr ocessesoft r
anscr ipt i
onand
transl ati
on.Thesebot hi nv olver ibonucl eicaci d, asi ngl e-st randedmol ecul esi mi l
ar
toDNAex ceptt hati thasar ibosesugarandaur acil baser athert hant hy mi ne.
Int hepr ocessoft ranscr iption, RNApol ymer aseI Ibi ndst oapr omot ersi tenear
the5' endofageneont henon- templ at est randand, thr oughcompl e¬ment arybase
pai r
ing, helpst opr oduceanmRNAst r
andf rom t het empl ateDNAst r
and
Somegenes—af ai r
lysmal lpropor tion—ar etr anscr ibedi nal lcell
soft hebody .
Thesehousekeepi nggenesencodepr oduct st hatar er equi redf orthecel l'
s
mai nt enanceandmet abol i
sm.Howev er ,mostgenesar et ranscr ibedonl yi nspeci fi
c
ti
ssuesatspeci ficpoi ntsi nt ime.Soonl yasmal l propor tionofgenesar eact iv el
y
tran¬scr ibed.Thi sspeci fi
cityexpl ainswhyt her ei sal argev ari
etyofdi f f
er entcel l
typesmaki ngdi ffer entpr oteinpr oduct s, event houghnear l
yal lcel l
shav eexact l
ythe
sameDNAsequence.Forexampl e, thegl obingenesar et ranscr ibedonl yi nt he
progeni tor sofr edbl oodcel ls( wher et heyhel pt of orm hemogl obin),andt hel ow-
densi tylipopr ot ein( LDL)r ecept orgenesar et ranscr ibedonl yinlivercel ls.
Tr anscr i
pt ionf act orsar er equi redf ort het ran¬scr ipt i
onofDNAt omRNA.These
i
ncl udegener al transcr iptionf act or st hatar eut ilizedbyal l genesaswel lasspeci f
ic
transcr i
pt i
onf act or st hathel pt oi nitiatet het ranscr i
pt ionofgenesi nspeci ficcel l
typesatspeci f i
cpoi ntsi nt i
me.
Tr anscr i
pt i
oni sal sor eg¬ul atedbyenhancerandsi l
encersequencest hatmaybe
l
ocat edt housandsofbasesawayf rom t hegene.
Thepr i
mar ymRNAt ranscr i
pti sexact lycompl ement aryt ot hebasesequenceof
theDNAt empl at e.I neukar yot es, ani mpor tantst ept akespl acebef oret hisRNA
transcr i
ptl eav est henucl eus.Sect ionsoft heRNAar er e¬mov edbynucl ear
enzy mes, andt her emai ningsect ionsar espl icedt oget hert ofor mt hef unct i
onal
mRNAt hatwi l
lmi gr at et ot hecy topl asm.Theexci sedsequencesar ecal ledi ntrons,
andt hesequencest hatar el efttocodef orpr ot einsar ecal l
edexons.
Onl ywhengenespl icingi scompl eteddoest hemat ur et ranscr i
ptmov eoutoft he
nucl eusi ntot hecy topl asm.
Somegenescont ainal ternat ivespl icesi t
es, whi chal l
owt hesamepr imar y
transcr i
ptt obespl icedi ndi fferentway s, ulti
¬mat elypr oduci ngdi ff
erentpr ot ein
product sf r
om t hesamegene.
Er rorsingenespl icing, l
iker epl icat ioner rors, ar eaf orm ofmut at i
ont hatcan
l
eadt ogenet i
cdi sease.
Transcri
pti
onofDNAt omRNA.RNApol ymer aseI
IproceedsalongtheDNAst r
and
i
nt he3'to5'dir
ect
ion,assembli
ngastrandofmRNAnucl eot
idesthatis
comple¬ment ar
ytotheDNAt emplat
est r
and.Theintron-
exonstruct
ureisakey
featur
eofmosteukar y
ot i
cgenes.Pr
esently
,thefunct
ionofintr
ons,ifany,
is
unknown.
TheGenet i
cCode
Proteinsarecomposedofoneormor epol ypeptides, whichareinturncomposed
ofsequencesofami noacids.
Thebodycont ai
ns20di ffer
enttypesofami noaci ds,andt heaminoaci d
sequencest hatmakeup
Becauset hereare20diff
erentami noacidsandonl yf ourdiffer
entRNAbases, a
singlebasecouldnotspeci f
yeachami noaci d.Simi l
ar l
y,specif
icaminoaci dscould
notbedef i
nedbycouplet
sofbases( e.
g.,adeninef ol¬lowedbyguani ne, oruraci
l
foll
owedbyadeni ne)be¬causeonl y16(4X4)di fferentcoupl etsar
epossi ble.If
tri
pletsetsofbasesaretranslatedint
oami no
acids,how¬ev er
,64(4X4X4)combi nationscanbeachi eved—mor et hanenough
tospeci f
yeachami noacid.
Thecor r
espondencebet weenspecifi
ccodonsandami noacids,
knownast he
genet i
ccode,isshowninTabl ebelow

Ala,Al anine;
Ar g,
argini
ne;Asn,asparagine;Asp,aspart
icaci
d;Cy s,cy
steine;Gi
n,
glutamine; Gla,gl
utamicacid;Gly,gl
yci
ne; His,hi
sti
-di
ne;He,i
soleucine;Leu,l
euci
ne;
Lys, l
ysine; Met,methi
onine;Phe,phenylalani
ne;Pro,pr
oli
ne;Ser
, seri
ne;Thr,
threonine; Trp,
trypt
o-phan;Tyr,
tyrosi
ne; Val,v
ali
ne.
 Ofthe64possi bl
ecodons,3signal
theendofageneandar eknownasstop
codons.TheseareUAA,UGA, andUAG.Theremaini
ng61allspeci
fyaminoaci
ds.
Thismeanst hatmostaminoacidscanbespeci
fi
edbymor ethanonecodon.
Whil
eagi venaminoacidmaybespecifi
edbymorethanonecodon,eachcodon
candesignat
eonlyoneami noacid.

Humangeneticpr
ogram amountt
o6bi l
l
ionbase-
pai
r(bp)ofDNA( twocopi
es)i
t
encode50000genes.
Eachgenee.g.a1400bpi sl
i
kelyt
oproduce30000deferentpr
otei
nsby
changi
ngsit
esofspli
cing,
sitei
fst
art
ingtr
anscr
ipt
ionandsit
eofterminat
ion.

Mutati
ons- --
--
-areanal t
erat
ioninDNAsequencetheyaretheul
ti
mat
esour
ceof
genet
icvariat
ion.
Somemut ati
ons---
--resul
tingeneti
cdisease dependingont
hesi
teoft
he
mutat
ion
Others--
--
--
--
---havenophy si
cal
effect
s. Onthegenome

Ty
pesofmut
ati
ons:

 Poi ntmut ati

on: whichi ssubst ati
onofonenucl eot i
def oranot herwi thi
nagene
thesei nclude:Mi ssense- -
---substationofonebppr oduceachangei nasi ngle
ami noaci dl i
ke
InSicklecel ldisease, whichcausesanemi a,tissueinf arct i
ons, and
mul tiple
inf
ections, isther esultofasi nglemi ssensemut at
iont hatpr oduces
anami no
acid(v ali
nesubst itut
egl utamicacidatposi ti
on6i ntheβ- globi n
chai n).
Non¬sense- ---
--whenmut at
ionpr oduceoneoft het hreest opcodonsi n
them RNA
whicht ermi natet r
ansl ati
onoft hemRNA.E. g.α-thalassemi a
condi tionsar e
usuallycausedbydel et i
onsofα- gl
obingenes.Thel ossoft hr eeof
these
genesl eadst omoder atel
ysev ereanemi a, andt helossofal lfouris
fatal.
Splicesit
emut at i
on-----whenmut ati
onoccurati ntron-exonboundar ies
alt
ert he
spli
cingsi gnal necessar yforproperexci sionofani ntron.
 Del etion/i nsert
ion: al oss/gai nofDNAsequencet hatr angef r
om si ngleBpt o
largepar tofchr omosome.I fno.ofBpaf f
ect edisnomul ti
pleof3- --
---Fr ame
shi ftmut at i
oni.e.itcanal terall t
hedownst ream codons.
 Dupl i
cation/Del et
ionofwhol egene: mayr esultinmor et han2copi esoft he
 samewhol egenet henr esulti
nincreaseproducti
onofcer t
ainprotein
 Trinucleoti
der epeatex pansion:Therepeatunitsarethreebaseslong, soa
typicalexampl ewoul dbeCAGCAGCAG.Anor malindi
vi
dualwi l
lhav ear ela¬ti
vel
y
smal lnumberoft heset andem repeats(e.
g.,20to30)ataspeci fi
cchr omosome
l
ocat ion.Forreasonst hatar enotyetunderstood,thenumberofr epeat scan
i
n¬cr easedr amat i
call
ydur ingmeiosisorpossiblyduri
ngearlyfetaldev elopment,
sot hatanewbor nmayhav ehundredsorev enthousandsofrepeat s.Whent hi
s
oc¬cur sincertainregionsoft hegenome, itcausesgeneticdisease.E.g.f ragi
leX
chromosome(CGGt andeml yrepeatedwithinagene)
:
 Mut ati
oncanresulti
n:
Gainoff uncti
onorlossoffunct i
onoft hepr otei
nproduct.
Gai n-
of-
funct
ionmutati
onsar esomet i
messeeni ndomi ¬nantdiseases.
Lossoff unct
ionisseenin( 1)recessi
v ediseases;
2)di
( seasesinvol vi
nghaplo-i
nsuffi
ciency,inwhich50%
ofthe
genepr oducti sinsuf
fi
cientfornormalf uncti
on;
(3)domi nantnegat i
vemuta¬tions,i
nwhi cht heabnor
mal
protein
productinter¬fereswiththenormalpr oteinproduct
.

CausesofMutati
on
Manysubstancesinourenvironmentareknownt obemut agenic.Theseincl
ude
i
onizi
ngandnon-ioni
zi
ngradiati
on, aswellashundredsofdiff entchemi
er cal
s.
Thesemutagensarecapableofcausi ngbasesubstit
utions,
delet
ions, and
fr
ameshif
ts.I
on¬izi
ngradi
ationcani nducedouble-
strandedDNAbr eaks.
Mutagensoccureit
hernaturall
y,
orgener
atedbyhumans.

Loci---
---
---
-theposi ti
onofgeneonachr omosome.
All
eles----
--
--thedi fferi
ngoft heDNAsequencesamongi ndivi
dualsasar esul
tof
mutat i
on.
Genot ypeofi ndi vidual--
--
--
--referst otheirgeneticmakeupi .
e.sequencesoft hei
r
genes.
Phenot ypeofi ndi vidual--
--
--
--descr ibeanyaspectofst r
uct ur
e,developmentof
pathophy si
ologyinani ndi
vidual.
Penet r
ance- ---
-t hepr oport
ionofi ndi vi
dualsinapopul ati
onpocessi ngthediseased
gene
(genot ype)whoex presst hediseasephenot ype.
Themut ati
onissai dt obef ull
ypenet r
ancei falli
ndiv
idualswho
i
nheritit,
dev elopstheassoci ateddi seasephenot ype e.g.neurofi
bromatosis
Expr essions- ---
---
descr i
bethedegr eet owhicht heseverit
yoft hedisease
phenot ypemayv ar y
.
e.g.forvari
ableex pr essivediseaseisTuber oussclerosi
s.