3

Mc lc
Li ni u 11
Hong Trng Phn

M u
I. Khi nim di truyn hc II. Lc s pht trin ca di truyn hc III. i tng v cc lnh vc nghin cu ca di truyn hc IV. Cc phng php nghin cu ca di truyn hc V.Cc nguyn tc nghin cu v phng php hc tp di truyn hc VI. Di truyn hc vi cng ngh sinh hc, tin hc v cc vn x hi 13 13 13 17 18 20 21 24 24 25 25 26 26 26 27 28 28 28 29 30 31 32 33 33 34 39

Chng 1: C s ca Di truyn hc Mendel

Hong Trng Phn

I. Tiu s Mendel - Cha ca di truyn hc II. i tng v phng php th nghim ca Mendel 1. i tng 2. Phng php III. Lai mt tnh v nguyn l phn ly 1. Kt qu th nghim lai mt tnh 2. Gii thch v kim chng nguyn l phn ly 3. Nguyn l phn ly v tnh ph bin ca n IV. Lai hai tnh v nguyn l phn ly c lp 1. Kt qu th nghim lai hai tnh 2. Gii thch v ni dung nguyn l phn ly c lp V. S di truyn Mendel ngi 1. Cc tnh trng ln 2. Cc tnh trng tri VI. L thuyt xc sut trong d on v phn tch di truyn hc 1. Mt s khi nim v tnh cht c bn ca xc sut 2. Mt s nguyn l xc sut c bn VII. Phng php 2 (Chi-square method) trong nh gi ph hp gia cc s liu quan st v k vng

Chng 2: M rng v p dng ca Di truyn hc Mendel

Hong Trng Phn

I. Cc kiu quan h gia cc gene allele i vi mt tnh trng 1. Cc kiu tri hon ton, khng hon ton v ng tri 2. Tc ng ca gene gy cht (lethals) 3. Hin tng a allele (multiple allelism) II. Tnh a hiu ca gene (pleiotropy) III. Cc kiu tng tc gia cc gene khng allele 1. Tng tc b tr (complementary) 2. Tng tc t ch (epistasis) 3. Tng tc cng gp- s di truyn a gene v cc tnh trng s lng IV. Cc mi quan h kiu gene - kiu hnh 1. Thng bin v mc phn ng 2. thm nhp (penetrance) v biu hin (expressivity)

43 43 43 45 46 47 48 49 52 54 59 59 60

Chng 3: C s T bo ca s Sinh sn, Di truyn v Bin d

Hong Trng Phn

I. Sinh sn hu tnh v tnh n nh ca cc b nhim sc th II. Hnh thi hc nhim sc th eukaryote 1. Kch thc nhim sc th 2. Tm ng v cc kiu nhim sc th 3. Cc kiu bng nhim sc th (chromosomal bands) III. Chu k t bo v nguyn phn 1. Chu k t bo (cell cycle) 2. Nguyn phn (mitosis) IV. Gim phn, s pht sinh giao t v th tinh 1. Gim phn (meiosis) 2. S pht sinh giao t (gametogenesis) 3. S th tinh (fertilization) V. Cc bin i ca nhim sc th 1. Cc bin i v cu trc nhim sc th 2. Cc bin i v s lng nhim sc th

67 67 70 70 71 72 74 75 76 78 78 81 83 84 84 91

Chng 4: Di truyn hc Nhim sc th

Hong Trng Phn 103

I. Trng phi Morgan vi thuyt di truyn nhim sc th 1. Tm quan trng ca rui gim Drosophila 2. Thuyt di truyn nhim sc th II. S xc nh gii tnh (sex determination) 1. S xc nh gii tnh do kiu gene (GSD) 2. S xc nh gii tnh do mi trng (ESD) III. S di truyn lin kt vi gii tnh (sex-linked inheritance) 1. c im di truyn ca cc gene trn nhim sc th X v Y 2. S bt hot ca nhim sc th X v mt s vn lin quan 3. Cc tnh trng gii hn bi gii tnh v chu nh hng ca gii tnh IV. Lin kt v ti t hp ca cc gene trn mt nhim sc th 1. Khm ph v s trao i cho rui gim 2. Lin kt gene hon ton (gim phn khng c trao i cho) V. Trao i cho v lp bn di truyn 1. Tn s ti t hp 2. Bn di truyn 3. Trao i cho bn si VI. Lp bn gene t cc php lai phn tch ba im 1. Trao i cho kp vi vic xc nh trt t v khong cch cc gene 2. nhiu v h s trng hp (coefficient of coincidence) VII. Lp bn bng phn tch b bn (tetrad analysis)

103 103 107 108 108 112 113 113 117 120 121 122 124 125 125 127 131 134 134 137 139

Chng 5: Bn cht Ho hc v Ti bn ca Vt cht Di truyn

Hong Trng Phn 147

I. Bng chng vt cht di truyn l cc nucleic acid 1. Cc th nghim bin np vi khun 2. Tnh n nh ca hm lng DNA cc sinh vt bc cao 3. Cc th nghim virus II. Thnh phn ho hc v cu trc ca DNA 1. Cu trc ca mt nucleotide

147 147 148 149 150 150

2. Cu trc chui polynucleotide 3. Thnh phn ho hc v cu trc ca chui xon kp DNA 4. S lc v cc c tnh ho l ca cc nucleic acid III. Kch thc b gene v tnh phc tp v mt tin ho 1. S lc v b gene ca cc virus, prokaryote v eukaryote 2. Mi quan h gia kch thc b gene v tnh phc tp v tin ho 3. Hm lng DNA v nghch l gi tr C 4. V kch thc DNA cc bo quan IV. T chc phn t ca cc nhim sc th 1. Cu trc cht nhim sc 2. S lc cc thnh phn DNA trong b gene eukaryote V. Ti bn DNA (DNA replication) 1. Cc nguyn tc v c im chung ca ti bn DNA 2. Cc enzyme tham gia ti bn DNA 3. C ch ti bn DNA VI. Ti bn ca cc b gene RNA (RNA genomes) 1. c im ti bn ca cc b gene RNA virus 2. Ti bn ca b gene RNA 3. Phin m ngc

151 152 155 157 157 159 159 161 161 161 163 164 164 167 168 174 174 174 175

Chng 6: Gene v Qu trnh Sinh tng hp Protein

Hong Trng Phn 179

I. S pht trin ca khi nim gene 1. Cc quan nim ca Mendel v Morgan v gene 2. Gi thuyt mt gene - mt enzyme ca Beadle v Tatum 3. Quan nim ca Benzer v cc n v cu trc v chc nng di truyn 4. Mi quan h gene - cistron cc prokaryote v eukaryote II. Cu trc v chc nng ca protein 1. Cu trc protein 2. Chc nng protein III. M di truyn 1. Bng chng di truyn hc v m b ba 2. Gii m di truyn

179 179 180 180 182 186 186 187 189 190 190

3. Cc c tnh ca m di truyn 4. Nhng ngoi l so vi m di truyn "ph bin" 5. S linh hot trong vic kt cp anticodon-codon IV. C ch phin m (transcription) v sa i sau phin m 1. Cc RNA v c im chung ca phin m 2. Cc RNA polymerase ca prokaryote v eukaryote 3. Cc promoter cc prokaryote v eukaryote 4. Cc giai on ca qu trnh phin m 5. S sa i sau phin m i vi cc mRNA eukaryote V. Cu trc v chc nng ca cc loi RNA v ribosome 1. RNA thng tin (messenger RNA = mRNA) 2. RNA vn chuyn (transfer RNA = tRNA) 3. RNA ribosome (ribosomal RNA = rRNA) 4. Ribosome VI. C ch dch m (translation) 1. Hot ho amino acid 2. C ch ca qu trnh dch m (tng hp polypeptide)

191 192 193 194 194 196 196 197 198 200 200 200 201 201 202 202 202

Chng 7: S iu ho Biu hin ca Gene

Trng Th Bch Phng 208

I. Cc nguyn l iu ho v mc kim sot phin m II. iu ho biu hin gene prokaryote 1. Cu trc ca operon 2. iu ho dng tnh operon lactose 3. iu ho m tnh operon tryptophan 4. Phin m d (attenuation) III. iu ho biu hin gene eukaryote 1. S bin i DNA 2. Cc promoter 3. Nhng trnh t tng cng phin m (enhancer) 4. Trnh t bt hot gene (gene silencing) 5. Promoter chn lc (alternative promoter) 6. Splicing chn lc

202 209 210 212 213 215 217 218 218 219 220 220 220

Chng 8: t bin Gene, Ti t hp v cc Yu t Di truyn Vn ng

Trng Th Bch Phng 223

I. t bin gene 1. Cc kiu t bin gene 2. Cc tc nhn gy t bin gene 3. C ch phn t ca cc t bin gene II. Sa cha v bo v DNA III. Cc yu t di truyn vn ng (transposable genetic elements) 1. Cc yu t di truyn vn ng prokaryote 2. Cc yu t di truyn vn ng eukaryote

223 223 228 228 232 237 237 239

Chng 9: S Di truyn T bo cht

I. S di truyn t bo cht 1. S di truyn ca cc gene lp th 2. S di truyn ca cc gene ty th 3. Hiu qu dng m ln chiu xon v c II. Lp bn ty th v lp th 1. Lp bn gene ca DNA lp th 2. Lp bn gene ca DNA ty th III. Di truyn hc phn t cc bo quan 1. Cc b gene lp th (cpDNA) 2. Cc b gene ty th (mtDNA)

Trng Th Bch Phng 245

245 245 246 249 251 251 253 254 254 255
Hong Trng Phn 258

Chng 10: i cng v Cng ngh DNA Ti t hp

I. Cc cng c chnh ca k thut to dng DNA ti t hp 1. Cc enzyme gii hn 2. Cc vector thng dng trong k thut di truyn 3. Thit lp phn t DNA ti t hp in vitro II. To dng gene hay DNA ti t hp 1. Nguyn tc chung 2. Quy trnh to dng gene ti t hp 3. Tng hp v to dng cDNA 258 258 260 261 263 263 264 267

III. Cc phng php biu hin cc gene c to dng IV. ng dng ca cng ngh DNA ti t hp 1. Cng ngh DNA ti t hp vi vic nghin cu b gene 2. Cng ngh DNA ti t hp vi y-dc hc 3. K thut di truyn vi cc sinh vt bin i gene

267 269 269 271 274

Chng 11: Di truyn hc Ngi

Trn Quc Dung 278

I. Cc phng php nghin cu di truyn hc ngi 1. Phng php phn tch ph h (genealogy analysis) 2. Phng php nghin cu tr sinh i 3. Phng php di truyn t bo hc ngi 4. Phng php nghin cu qun th 5. Cc k thut sinh hc phn t II. Cc phng php lp bn di truyn ngi 1. Phn tch lin kt (linkage analysis) 2. Cc phng php lp bn vt l (physical mapping) III. Nhim sc th Y v cht nhim sc gii tnh ca ngi 1. Nhim sc th Y ca ngi 2. Cht nhim sc th gii tnh ca ngi IV. S di truyn cc gene tri-ln trn nhim sc th thng v nhim sc th gii tnh 1. S di truyn cc gene tri-ln trn nhim sc th thng 2. S di truyn cc gene tri-ln trn nhim sc th gii tnh V. Di truyn y hc 1. Cc bnh di truyn do ri lon chuyn ho v cc bnh nhim sc th 2. C s di truyn ung th VI. T vn di truyn y hc

278 278 279 279 279 280 280 280 280 283 283 284 285 285 286 288 288 291 292

Chng 12: Di truyn hc Qun th

Hong Trng Phn 296

I. Cc khi nim c bn ca di truyn hc qun th 1. Qun th (population) 2. Cc h thng giao phi

296 296 296

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3. Vn gene (gene pool) 4. Tn s kiu gene v tn s allele II. Nguyn l Hardy-Weinberg v trng thi cn bng ca qun th 1. Nguyn l Hardy-Weinberg 2. Nhng ng dng ca nguyn l Hardy-Weinberg III. M rng nguyn l Hardy-Weinberg 1. a allele (multiple alleles) 2. Tn s allele sai bit gia hai gii tnh 3. Cc gene lin kt trn X IV. Ni phi (inbreeding) 1. T th tinh (self-fertilization) 2. H s ni phi (inbreeding coefficient) 3. Tnh ton h s ni phi V. Cc nhn t tc ng ln thnh phn di truyn qun th 1. t bin 2. Bin ng di truyn ngu nhin 3. Dng gene hay s di nhp c 4. Chn lc t nhin

297 297 299 299 302 305 305 308 309 310 311 312 313 315 315 316 316 318

11

Li ni u
n nay, di truyn hc ra i ch mi hn mt trm nm song n pht trin vi mt tc ht sc nhanh chng. c bit l, trong vng 50 nm li y k t ngy James Watson v Francis Crick khm ph ra cu trc phn t DNA, 25/4/1953. S hon thnh vic gii m di truyn bi hai nhm nghin cu ca Marshall Nirenberg v Har Gobind Khorana vo thng 6 nm 1966 v s ra i ca K thut Di truyn v Cng ngh DNA ti t hp vo gia thp nin 1970 l hai s kin ni bt nht k t sau khi sinh hc phn t ra i. K , s hon tt ca D n B gene Ngi vo thng 4 nm 2003 c xem l mt trong nhng k cng thm him v i nht ca loi ngi. Ln u tin con ngi c th c c mt cch y ton b trnh t 3.164.700.000 cp base trong b gene ca mnh. Tt c nhng s kin ni bt ny minh chng mt iu rng: S pht trin cng vi nhng thnh tu t c ca di truyn hc trong thi gian qua qu l v cng to ln! gp phn i mi ni dung gio trnh Di truyn hc theo hng cp nht kin thc cng nh phng php dy v hc b mn bc i hc, chng ti tham cu nhiu ti liu khc nhau v n lc bin son gio trnh trn tinh thn y. Chng ti hy vng rng gio trnh ny s p ng c phn no nhu cu ging dy v hc tp ca ging vin v sinh vin, v cng c th s dng nh mt ti liu tham kho b ch cho gio vin Sinh hc cc trng THPT trong bi cnh i mi gio dc hin nay. Ni dung gio trnh gm phn M u cng vi 12 chng bao qut cc kin thc i cng ca mt gio trnh Di truyn hc. Cc chng 14 cp ch yu ni dung thuc Di truyn hc c in, cc chng 5-10 tp trung vo phn Di truyn hc phn t v chng 12 c xem l phn nhp mn ca Di truyn hc qun th, cn chng 11 l s kt hp gia cc kin thc di truyn c in v hin i trn i tng l con ngi. Cui mi chng u c cc phn Cu hi v Bi tp v Ti liu Tham kho bn c tin n tp v tra cu. Gio trnh Di truyn hc c ra i trong khun kh ca D n Gio dc thuc i hc Hu, v vy mt s kin thc nng cao s c cp trong mt gio trnh ring, nh: Di truyn Vi sinh vt v ng dng,v Cng ngh DNA Ti t hp. Bn cnh , mt s thut ng khoa hc c thng nht s dng bng ting Anh gip ngi hc d dng hn trong vic tip cn vi thng tin qua sch bo nc ngoi hoc internet.

12

Gio trnh ny do ThS. Hong Trng Phn (ch bin), TS. Trng Th Bch Phng v TS. Trn Quc Dung l nhng ging vin ang cng tc ti Khoa Sinh hc cc trng i hc S phm v i hc Khoa hc thuc i hc Hu bin son, vi s phn cng nh sau: ThS. Hong Trng Phn bin son phn M u v cc chng 1, 2, 3, 4, 5, 6, 10 v 12; TS. Trng Th Bch Phng bin son cc chng 7, 8 v 9; v TS. Trn Quc Dung bin son chng 11. gio trnh ny kp thi ra mt bn c, chng ti xin trn trng cm n D n Gio dc i hc Hu ti tr cho vic bin son v xut bn gio trnh trong khun kh ca D n Gio dc i hc mc B. Chng ti xin by t lng cm n c bit n GS. TS. Phan C Nhn, Trng i hc S phm H Ni, dy cng c bn tho v cho nhiu kin qu bu cng nh khch l chng ti rt nhiu k t khi cng gio trnh bt u c hnh thnh. Do kh nng cn hn ch, chc chn gio trnh cn nhiu thiu st. Chng ti rt mong nhn c s ph bnh v ch bo ca cc ng nghip v bn c gio trnh c hon chnh hn trong ln in sau. Hu, ngy 25 thng 6 nm 2005 Cc tc gi

13

M u
I. Khi nim di truyn hc
Theo quan nim ca Bateson (1906), di truyn hc (genetics) l khoa hc nghin cu cc c tnh di truyn v bin d vn c ca mi sinh vt cng vi cc nguyn tc v phng php iu khin cc c tnh . y, tnh di truyn (heredity) c biu hin s ging nhau gia con ci vi cha m; v tnh bin d (variability) biu hin s sai khc gia cha m v con ci cng nh gia cc con ci vi nhau. Cn lu rng, gene l khi nim cn bn ca di truyn hc cho nn ni dung ca khi nim gene khng ngng c pht trin cng vi s pht trin ca di truyn hc.

II. Lc s pht trin ca di truyn hc

S ra i v pht trin ca di truyn hc gn lin vi cng trnh nghin cu ca Gregor Mendel nm 1865. Tuy nhin, trc thi Mendel c bit l t th k XVII c mt s s kin quan trng sau y: (1) S ra i ca knh hin vi s khai bi A.van Leuvenhook (1632-1723); v (2) Sinh hc bt u pht trin mnh vo th k XIX vi s ra i thuyt t bo ca M.Schleiden v T.Schwann (1838,1839) v cc thuyt tin ha ca J.B.Lamarck (1809) v c bit l ca R.C.Darwin (1859). Nhn chung, quan nim ph bin thi by gi vn l s di truyn cc tnh trng tp nhim (inheritance of acquired characters) do Lamarck xut v s di truyn ha hp (blending inheritance), ngha l s pha ln "tinh cha huyt m" con ci. 1. S ra i v pht trin ca di truyn Mendel T u H Lan (Pisum sativum), vi tng v phng php nghin cu c o, nm 1865 Gregor Mendel (Hnh 1) pht hin ra cc quy lut di truyn c s u tin v qua suy ra s tn ti tt yu ca cc n v i truyn c th - nhn t di truyn (genetic factor) - quy nh cc tnh trng c truyn t th h ny sang th h khc m sau ny gi l gene. Tuy nhin, gii khoa hc ng thi khng hiu v do khng th nh gi tm vc v i ca pht minh ny. Hnh 1 G. Mendel Mi n nm 1900, ba nh thc vt hc l Carl Correns (Germany), Hugo de Vries (Netherlands) v Erich von Tschermak (Austria) c lp nhau khm ph li cc quy lut di truyn ca Mendel. V di truyn hc chnh thc ra i t y m ngi sng lp l Mendel.

14

Trong nhng nm u th k XX, nh ng dng di truyn Mendel, cc nh chn ging pht hin thm cc hin tng nh: tri khng hon ton, ng tri, gene gy cht, a allele, cc kiu tng tc gene... giai on ny, ngoi thuyt t bin ca H.de Vries nm 1901, cn c hai s kin lin quan n s ra i ca thuyt di truyn nhim sc th v di truyn hc qun th sau ny, l s khi xng "thuyt nhim sc th" bi Walter Sutton v Theodor Bovary nm 1902 v vic thit lp quy lut Hardy-Weinberg nm 1908. Mt s thut ng thng dng cng c xut trong giai an ny, nh: di truyn hc (genetics) bi W.Bateson nm 1906, gene, kiu gene (genotype) v kiu hnh (phenotype) bi W.Johannsen nm 1909. 2. S ra i v pht trin ca thuyt di truyn nhim sc th T 1910, Thomas Hunt Morgan (Hnh 2) cng vi ba cng s l Alfred H.Sturtevant, Calvin Bridges v Herman J. Muller xy dng thnh cng thuyt di truyn nhim sc th (chromosome theory of inheritance) da trn i tng nghin cu l rui gim Drosophila melanogaster. Hc thuyt ny xc nhn rng gene l n v c s ca tnh di truyn nm trn nhim sc th ( trong nhn); trn cc gene sp xp theo ng thng
Hnh 2 T.H.Morgan

to thnh nhm lin kt. Nhng ng gp ng k ca cc mn xut sc ca Morgan l: xy dng bn di truyn (Sturtevant 1913), ch ra c ch xc nh cc kiu hnh gii tnh rui gim (Bridges 1916) v pht trin phng php gy t bin bng tia X (Muller 1927). Vi ng gp to ln Morgan c trao gii Nobel nm 1933 v Muller nm 1946. Nm 1931, Barbara McClintock (Hnh 3) v Harriet Creighton thu c bng chng vt l trc tip v ti t hp ng. Sau , hin tng ny cng c C. Stern quan st Drosophila. Nh vy ti t hp c th c pht hin c v mt vt l ln di truyn ng vt cng nh thc vt. n 1944, McClintock pht hin cc yu t di truyn vn ng (transposable genetic elements), v b c trao gii Nobel nm 1983 v khm ph ny.
Hnh 3 B.McClintock

3. S ra i v pht trin ca di truyn hc phn t S ra i ca di truyn hc phn t (molecular genetics) gn lin vi cc khm ph v DNA (deoxyribonucleic acid) t gia th k XX trn i

15

tng nghin cu ch yu l cc vi sinh vt. Tuy nhin, trc Friedrich Miescher (1869) khm ph ra mt hn hp trong nhn t bo gi l nuclein m thnh phn chnh ca n sau ny c bit l DNA.

Hnh 4 Beadle, Tatum, Jacob v Monod (t tri sang)

V mi quan h gia gene v protein, t 1902 Archibald Garrod qua nghin cu bnh alcaptonuria ngi gi rng y l mt tnh trng ln Mendel, c th lin quan ti s sai hng mt enzyme. Bng cc th nghim gy t bin cc gene lin quan n cc con ng sinh ha trn nm mc Neurospora, nm 1941 George Beadle v E.L.Tatum (Hnh 4) xc nhn mi gene kim sot s tng hp mt enzyme c th. Chnh gi thuyt mt gene-mt enzyme (one gene-one enzyme hypothesis) ni ting ny m ng cho s ra i ca di truyn ha-sinh, v hai ng c trao gii Nobel cng vi Joshua Lederberg nm 1958. V sau, gi thuyt ny c chnh xc ha l mt gene xc nh ch mt chui polypeptid cu trc s cp ca cc protein, trong c cc enzyme. Vy bn cht ca gene l g? Nm 1944, Oswald Avery (Hnh 5) v cc cng s l MacLeod v McCarty bng th nghim bin np in vitro chng minh rng DNA l vt cht mang thng tin di truyn. Nm 1949, Erwin Chargaff cng b cc kt qu u tin v thnh phn ha hc ca DNA mt s loi.
Hnh 5 O.T. Avery

Vic nghin cu cu trc phn t DNA c bt u t 1951 vi cc dn liu nhiu x tia X ca Rosalind Franklin v Maurice Wilkins (Hnh 6). Cc s liu ha hc v vt l ny l c s m t James Watson v Francis Crick (Hnh 7) xy dng thnh cng m hnh cu trc phn t DNA nm 1953, cn gi l chui

Hnh 6 R.Franklin (tri) v M.Wilkins

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xon kp (double helix). Pht minh v i ny m ra k nguyn mi cho s pht trin ca di truyn hc v sinh hc ni chung. Vi pht minh , Watson v Crick cng vi Wilkins c trao gii Nobel nm 1962 . Bi bo nhan "Mt cu trc cho Deoxyribose Nucleic Acid" ca Watson v Crick ng trn tp ch Nature ngy 25/4/1953 c nh gi
Hnh 7 J.D.Watson (tri) v F.H.C.Crick

l mt bi bo khng bnh thng. Ch vn vn c 128 dng nhng ng sau bi bo l c mt bc tin lch s v i ca di truyn hc m mi dng l mt cu chuyn. Tht vy, sau cu trc chui xon kp l hng lot cc khm ph mi. Nm 1958 Matthew Meselson v Franklin Stahl chng minh s ti bn bn bo ton ca DNA; v nm 1961 Seymour Benzer hon tt cng trnh nghin cu cu trc tinh vi ca gene; Francois Jacob v Jacques Monod (Hnh 4) tm ra c ch iu ha sinh tng hp protein (gii Nobel 1965 vi Andre Lwoff); S.Brenner, Jacob v Meselson khm ph ra RNA thng tin; S.Brenner v F.Crick chng minh m ditruyn l m b ba; cng trnh gii m
Hnh 8 H.G.Khorana (tri) v M.Nirenberg

di truyn ny c hon thnh vo thng 6 nm 1966 bi hai nhm nghin cu ca Marshall Nirenberg v Har Gobind Khorana (gii Nobel nm 1968; Hnh 8). 4. S ra i v pht trin ca cng ngh DNA ti t hp C th ni, nn tng ca cng ngh DNA ti t hp (recombinant DNA technology) c thnh lp t 1972 khi Paul Berg (Hnh 10) to ra phn t DNA ti t hp u tin trong ng nghim (recombinant DNA in vitro). Mt nm sau Herbert Boyer v Stanley Cohen (Hnh 10) ln u tin s dng plasmid to dng DNA. Lnh vc ng dng mi ny ca sinh hc phn t to ra mt cuc cch mng mi trong sinh hc. ng gp ng k trong lnh vc ny l khm ph v cc enzyme gii hn (restriction enzyme) t 1961-1969 ca Werner Arber, Daniel Nathans v

17

Hamilton Smith (gii Nobel 1978; Hnh 10); xut cc phng php xc nh trnh t base trong cc nucleic acid nm 1977 bi P.Berg, W.Gilbert

Hnh 9 Cc nh khoa hc ot gii Nobel y hc lin quan k thut gene. T tri sang: D.Nathans, H.Smith, W.Arber, P.Sharp v R.Robert.

Hnh 10 Cc nh khoa hc ot gii Nobel ha hc lin quan k thut gene. T tri sang: H.Boyer, S.Cohen, P.Berg, W.Gilbert, F.Sanger v K.Mullis.

v Frederick Sanger (gii Nobel ha hc 1980; Hnh 10); s khm ph ra cc gene phn on (split gene) nm 1977 bi Phillip Sharp v Richard Robert (gii Nobel 1993; Hnh 9); s pht minh ra phng php PCR (polymerase chain reaction) ca Kary B.Mullis nm 1985 (Hnh 10) v phng php gy t bin nh hng (site-directed mutagenesis) ca Michael Smith t 1978-1982 (gii Nobel ha hc 1993)... Cng vi nhng thnh tu ng dng ly k trong sn xut v i sng x hi, nh vic sn xut cc ch phm y-sinh hc bng cng ngh DNA ti t hp, s dng liu php gene (gene therapy) trong iu tr bnh di truyn, to cc ging sinh vt mi bng con ng bin i gene (genetically modified organisms = GMOs), d n b gene ngi (Human Genome Project = HGP)... gy ra khng t hoi nghi, tranh ci xung quanh cc vn v o l sinh hc (bioethics) v an ton sinh hc (biosafety).

III. i tng v cc lnh vc nghin cu ca di truyn hc

Trong giai on u, i tng ca di truyn hc l cc thc vt, ng vt, ngi v cc vi sinh vt. T dn ti s hnh thnh cc lnh vc nghin cu tng ng l di truyn hc thc vt, ng vt, ngi v di truyn hc vi sinh vt, trong di truyn hc t bo l c s. Giai on

18

ny ko di t thi Mendel cho n thp nin 1940, vi c trng l nghin cu quy lut di truyn cc tnh trng qua cc th h. V vy n thng c gi l giai on di truyn hc Mendel hay di truyn hc c in (Mendelian or classical genetics). T thp nin 1950 n nay, vi s ra i ca di truyn hc phn t (molecular genetics), i tng nghin cu l t chc, cu trc, chc nng v c ch hot ng ca cc b gene (genomes), cc gene v cc sn phm ca chng mc phn t. c bit vi s ra i ca cc k thut to dng gene (gene-cloning techniques) t thp nin 1970, vic nghin cu c bn cng nh ng dng tr nn ht sc thun li. S phn ha thnh cc chuyn ngnh lc ny l v cng phong ph v a dng, nh: di truyn hc bnh (genetics of disease), di truyn hc ung th (genetics of cancer), di truyn hc pht trin (developmental genetics), cng ngh sinh hc (biotechnology)...Gn y cn xut hin mt s lnh vc nghin cu mi nh genomics, DNA chip technology, DNA microarray technology... Mt hng khc ca di truyn hc chuyn nghin cu cu trc di truyn ca cc qun th v s bin i di truyn bn trong qun th v gia cc qun th. l nhnh di truyn hc qun th (population genetics), m nguyn l c s ca n c G.Hardy (England) v W.Weinberg (Germany) c lp a ra nm 1908. Tuy nhin, lnh vc nghin cu ny ch thc s bt u t thp nin 1930 vi cc cng trnh ca R.A.Fisher, J.B.S.Haldane v Sewall Wright. Ngy nay cc nh di truyn hc khng cn thin v nghin cu s bin i mc kiu hnh m tp trung vo s bin i phn t trong mt qun th nhm tm hiu ngha tin ha ca cc bin i . V nh th di truyn hc qun th tr thnh nn tng cho cc thuyt tin ha hin i. Qua phn tch trn cho thy ba nhnh chnh ca di truyn hc, l: di truyn hc Mendel, di truyn hc phn t v di truyn hc qun th.

IV. Cc phng php nghin cu ca di truyn hc

Vic nghin cu di truyn hc c tin hnh bi nhiu phng php khc nhau. Bn cnh cc phng php kinh in c th cn c s pht trin v tch hp ca cc phng php t ton hc, tin hc, vt l v ha hc c bit l trong lnh vc sinh hc phn t. 1. Cc phng php kinh in c th ca di truyn hc Trc ht l phng php t th phn dng chn cc dng thun lm b m trong cc php lai, cc phng php lai mt hoc ng thi nhiu tnh trng gia cc b m do Mendel xut. Trong bao gm c cc hnh thc lai thun nghch v lai phn tch (testcross) nhm rt

19

ra quy lut, kim tra kiu gene hoc dng thit lp bn di truyn. i vi nghin cu di truyn ngi v mt s vt nui giao phi cn huyt (consanguineous), c trng l phng php phn tch ph h (pedigree analysis) nhm xc nh c im di truyn tri-ln ca mt tnh trng hoc bnh tt; nghin cu tr sinh i cng trng v khc trng nhm xc nh h s di truyn (heritability) ca tnh trng; phng php gy t bin (mutagenesis) kt hp vi lai hu tnh dng trong nghin cu v chn to ging, c bit l thc vt... 2. Phng php ton hc Trong nghin cu khoa hc ni chung v di truyn hc ni ring, vic p dng cc cng c ton thng k v l thuyt xc sut phn tch nh lng v l gii cc kt qu nghin cu l rt thit yu. Chnh iu lm cho di truyn hc tr thnh mt khoa hc chnh xc v mang tnh d bo. iu ny th hin r trong cc cng trnh nghin cu ca Mendel, Morgan cng nh trong cc nghin cu di truyn s lng v di truyn qun th. 3. Cc phng php vt l v ha hc Trong nghin cu di truyn, c bit l di truyn phn t v t bo i hi phi s dng cc k thut v phng php ca vt l v ha hc. Chng hn, trong nghin cu hnh thi nhim sc th khng th thiu cc loi knh hin vi quang hc v in t, cc k thut nhum bng (banding techniques); nghin cu thnh phn ha hc v cu trc DNA i hi cc phng php sc k v nhiu x tia X... 4. Cc phng php t bo hc Trong nghin cu di truyn t bo c rt nhiu phng php c s dng quan st hnh thi nhim sc th v thit lp kiu nhn (karyotype) ca cc loi cng nh chn on cc bnh tt lin quan n s bin i s lng v cu trc nhim sc th. Bn cnh cc k thut nui cy m v chun b nhim sc th l cc k thut nhum bng khc nhau, k thut lai hunh quang ti ch (fluorescence in situ hybridization = FISH), k thut min dch t bo hc... (xem Verma v Babu 1995). 5. Cc phng php ca sinh hc phn t - k thut di truyn S tin b nhanh chng gn y ca sinh hc phn t v cng ngh sinh hc l nh s pht trin mnh m ca cc k thut ti t hp DNA, lai phn t, s dng cc mu d v phng php nh du khc nhau, phng php PCR, cc phng php xc nh trnh t nucleic acid cng nh cc phng php bin i vt liu di truyn mi. Vi cc cng c k thut mi ny cho php i su nghin cu t

20

chc ca cc gene v b gene, cc c ch iu ha v bin i di truyn mc phn t cng nh cc thnh tu ng dng mi trong y-sinh hc, nng nghip v cc lnh vc khc ca i sng-x hi. V. Cc nguyn tc nghin cu v phng php hc tp di truyn hc 1. Cc nguyn tc nghin cu ca di truyn hc Trong nghin cu di truyn hc v sinh hc ni chung c cc nguyn tc chung cn tun th nh l phng php lun, sau y: (1) Ly t bo lm n v nghin cu; (2) Thng tin di truyn cha trong b gene t bo chi phi mi biu hin sng ca n m cc gene l n v di truyn c s; (3) S hot ng ca cc gene trong qa trnh pht trin c th l c trng cho tng gene trong tng giai on c th; (4) Cc qu trnh trong cc h thng sng phi c iu ha v kim sot m bo cho s tn ti ca n l lin tc, trong ph bin l s t iu chnh bng cc c ch phn hi thng tin (feed-back mechanism); (5) S thng nht gia cu trc v chc nng biu hin tt c cc mc t chc khc nhau ca s sng; (6) Tt c cc t chc v qu trnh sng u tun theo cc quy lut vt l v ha hc; (7) S sng trn tri t tri qua qu trnh tin ha khong 3,5 t nm qua, v vy khi so snh, nhng nt tng ng gia chng cho thy tnh thng nht v mt ngun gc v nhng nt d bit cho thy tnh pht trin, s phn ha a dng tt yu ca chng. 2. Phng php hc tp mn di truyn hc Cng nh bt k mn hc no khc, vic hc tp mn di truyn i hi phi nm vng lch s mn hc, i tng, nhim v, phng php nghin cu v h thng kin thc cn bn ca n. Bn cnh cc nguyn tc ni trn vn rt cn cho t duy trong hc tp, di y nu mt s im chnh lin quan phng php hc tp c th ca b mn. (1) Nm vng cc kin thc lin mn (nh t bo hc, ha sinh hc, vi sinh hc, hc thuyt tin ha...) v lin ngnh (nh cc khi nim v nguyn l c bn ca ton thng k-xc sut, vt l v ha hu c). (2) Nm vng h thng khi nim c bn cng nh cc thut ng mi khng ngng ny sinh. Trong gene l khi nim cn bn c ni hm khng ngng pht trin, c bit l trong ba thp nin li y. (3) Hiu r bn cht ca cc nguyn l di truyn trong tng ch cng nh mi lin quan gia chng c th gii thch v vn dng trong gii quyt cc bi ton hoc tnh hung ca i sng v thc tin sn xut. (4) nm kin thc v pht trin cc k nng t duy mt cch vng chc i hi phi bit vn dng kin thc vo gii bi tp cng nh cc k nng thc hnh th nghim.

21

(5) Di truyn hc l mt khoa hc thc nghim, nn thng tin thu c l nh cc quan st t th gii t nhin, v phng php khoa hc chnh l cng c hiu bit cc quan st . Ni n phng php nghin cu khoa hc l ni n cc bc tin hnh theo mt trnh t t chc cng vic cht ch sau y: Quan st Gi thuyt D on Thc nghim ( kim tra gi thuyt t ra) xut gi thuyt mi. Cng cn lu rng, c tnh ca khoa hc l hoi nghi, i hi phi c bng chng xc thc, l kt hp gia logic v tr tng tng, l gii thch v d on, khng c s c on; ngi nghin cu hay nh khoa hc phi nhn bit sng t, trung thc, v t, v ni chung l chu s chi phi ca cc nguyn tc o c c tha nhn rng ri. (6) Trong khi hc gio trnh, bn nn lm t nht mt tiu lun v mt vn cp nht mnh yu thch. iu rt l th v b ch. Bi cng vic ny i hi s say m tm ti cc thng tin mi, c bit l trn mng vit mt bi tng lun c tnh khoa hc v trnh by trong mt seminar. (7) Bi di truyn hc l mt ngnh khoa hc non tr nhng pht trin vi tc cc nhanh, nn khi lng kin thc mi tch ly c l v cng phong ph v a dng. c th cp nht thng tin v mn hc i hi phi tng cng kh nng s dng ting Anh v internet. iu quan trng l phi to cho mnh mt hoi bo hc tp, mt kh nng v phng php t hc v thnh lp cho c mt th mc tra cu. Trong ng k l cc trang web (c gii thiu trong tng chng), hoc c th s dng ngay cc t kha (key words) c cho tng ch tm kim vi cng c c th ni mnh nht hin nay l Google. VI. Di truyn hc vi cng ngh sinh hc, tin hc v cc vn x hi Nh cp, s pht trin ht sc nhanh chng ca di truyn hc trong vi thp nin qua, c bit l s tin b ca cng ngh sinh hc (biotechnology) ni chung c nhng tc ng mnh m ln nhiu ngnh khoa hc v trn mi mt ca i sng, kinh t, chnh tr v x hi phm vi ton cu. Di truyn hc c hnh dung v tr trung tm v giao thoa vi sinh hc, ha sinh hc, k ngh, y-dc, nng nghip, sinh thi hc, kinh t hc, lut, x hi hc v trit hc. Gio s danh d mn ha hc i hc Havard, F.H.Westheimer, bnh lun v sinh hc phn t nh sau:"Cuc cch mng tr tu v i nht ca 40 nm qua xy ra trong sinh hc. Liu c th tm ra mt ngi no c hc ngy nay m khng hiu bit cht g v sinh hc phn t?" (dn theo Weaver v Hedrick 1997, tr.15). Cc thnh tu t c nh ng dng di truyn hc trong nng nghip

22

l v cng to ln, gp phn to nn cuc "cch mng xanh ln th hai" vi s ra i ca hng lot cc ging vt nui-cy trng c u th lai vt tri, cc sinh vt bin i gene (GMOs) mang nhng c tnh hon ton mi l. Trong y hc, l s ra i ca hng lot cc dc phm c sn xut bng k thut di truyn dng cho iu tr bnh v ci bin tr thng minh ca con ngi; l cc phng php chn on v iu tr bnh mc phn t...S thnh cng ca d n b gene ngi (HGP) vo thng 4 nm 2003 cho php chng ta ln u tin c c ton b trnh t khong 3,2 t cp nucleotide trong b gene con ngi (Homo sapiens). HGP l mt trong nhng k cng thm him v i nht trong lch s nhn loi (NHGRI 2005). Theo c tnh mi nht c cng b ngy 21/10/2004 trn tp ch Nature, b gene chng ta cha s lng gene m ha protein thp mt cch ng kinh ngc, khong 20.000 n 25.000 ch khng phi l 50.000 n 140.000 gene nh d on ban u hoc 35.000 theo d on trong vi ba nm li y (NHGRI 2005). Chnh s kt hp tin hc v my tnh trong nghin cu sinh hc phn t dn ti s ra i mt ngnh mi l sinh-tin hc (bioinformatics) cho php thu thp, t chc v phn tch s lng ln cc s liu sinh hc nh s dng mng my tnh v cc ngun d liu (databases). V mt s lnh vc nghin cu mi khc cng ra i nh: genomics - phn tch ton b genome ca mt sinh vt c chn, DNA microchip technology - xc nh cc t bin trong cc gene, DNA microarray technology - nghin cu cch thc mt s lng ln cc gene tng tc ln nhau v c ch mng li iu ha ca t bo kim sot ng thi s lng cc k ln cc gene... Nhng thch thc cho tng lai ca nghin cu khoa hc v cc b gene (genomics) i vi sinh hc, vn sc khe v x hi cng c t ra (Collins v cs 2003). S hon tt ca HGP t n khng c ngha l xong m ng hn l im khi u cho cng cuc nghin cu thm ch cn hng th hn. Cc nh nghin cu hin gi ang c gng lm sng t mt s qu trnh phc tp nht ca sinh hc, l: mt a b pht trin t mt t bo n l bng cch no, cc gene phi hp chc nng ca cc m v c quan nh th no, s tin nh bnh tt xy ra nh th no v b no ngi lm vic ra sao (NHGRI 2005). Cng vi nhng thnh tu ng dng ly k trong sn xut v i sng x hi ni trn, nhiu vn mi c t ra cho cc ngnh gio dc, lut, trit hc, x hi hc v gy khng t hoi nghi, tranh ci xung quanh cc vn v o l sinh hc, an ton sinh hc v mi sinh.

23

Ti liu Tham kho

Ting Vit H Hunh Thy Dng. 1997. Sinh hc Phn t. NXB Gio Dc. Phm Thnh H. 2000. Di truyn hc. Ti bn ln II, NXB Gio Dc. Phan C Nhn (ch bin), Nguyn Minh Cng, ng Hu Lanh. 1999. Di truyn hc. NXB Gio Dc. Ting Anh Collins FS, Green ED, Guttmacher AE, Guyer MS. 2003. A vision for the future of genomics research. Nature, Vol. 422, No. 6934, p.835-847. McKusick V. 1998. Mendelian Inheritance in Man. 12th ed., Johns Hopkins University Press, Baltimore. National Human Genome Research Institute (NHGRI)/ National Institute of Health (NIH). 2005: http://www.genome.gov/ http://www.ncbi.nlm.nih.gov/ Online Mendelian Inheritance in Man (OMIMTM): http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM Tamarin RH. 1999. Principles of Genetics. 6th ed, McGraw-Hill, Inc, NY. Verma RS and Babu A. 1995. Human chromosome : principles and techniques. 2nd ed, international edition, McGraw-Hill, Inc., New York. Watson JD and Crick FHC. 1953. A structure for Deoxyribose Nucleic Acid. April 25,1953, Nature, Vol.171, page 737. Weaver RF, Hedrick PW. 1997. Genetics. 3rd ed, McGraw-Hill Companies, Inc. Wm.C.Brown Publishers, Dubuque, IA. Zinnen T. 2005. JD Watson and FHC Crick - A structure for Deoxyribose Nucleic Acid - Nature, 25 April 1953. (http://www.accessexcellence.org)

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Chng 1

C s ca Di truyn hc Mendel
Cho n u th k XX, mi ngi cn cha hiu c c ch ca s di truyn, mc d vn bit rng con ci sinh ra thng ging b m. Quan nim ph bin cho n gia th k XIX c gi gn trong ci gi l thuyt di truyn ha hp (theory of blending inheritance) nhm gii thch s kin con ci mang cc c im ca c hai b m. Tuy nhin, n nm 1866 Gregor Mendel a ra thuyt di truyn gin on (theory of particulate inheritance), vi gi rng: n v di truyn c th kim sot mt tnh trng c truyn t th h ny sang th h khc tn ti di dng ht, ngy nay ta gi l gene. Cc khm ph quan trng ca Mendel t nn mng cho s ra i ca di truyn hc sau ny. Nh Thomas Hunt Morgan nhn nh: "Trong mi nm nghin cu cy u H Lan trong ngi vn ca tu vin, G. Mendel lm nn s khm ph v i nht trong sinh hc t c trong nm trm nm qua".

I. Tiu s Mendel - Cha ca Di truyn hc

Gregor Mendel sinh nm 1822, ln ln trang tri ca cha mnh ti mt tnh ca Austria (o). V gia nh ngho nn ng phi vo tu vin tip tc vic hc ca mnh. Trong khong thi gian ny, Mendel nghin cu vt l v ton l nhng mn hc gip ng nhiu trong cc th nghim di truyn sau ny. ng c gi ti i hc Vienna thi ly bng gio vin chnh thc, nhng khng v quay v tu vin "dy hc" trong nhiu nm.
Hnh 1.1 Gregor Mendel trong ngi vn ca tu vin Brno.

Khi cn trang tri ca cha mnh, Mendel quan tm ti cc cy ci v con vt, v thng gi li nhng ci hoa, con ong v chut. Sau ny tu vin Brno ng tp trung vo cc cy u H Lan (Pisum sativum). Mendel xc nh c cc nguyn l di truyn c s t cc th nghim chn ging thc vt. Cc kt qu nghin cu ny c Mendel trnh by nm 1865 trc Hi Nghin cu Khoa hc T nhin Brno v cng b nm 1866 Germany trong mt bi bo nhan l Cc th nghim lai thc vt (Experiments on Plant Hybrids). Bi bo ny nhanh chng c mt nhiu th vin, nhng nhng ngi cng thi ng khng

25

hiu c cc pht hin ca ng, c l mt phn l do ng s dng ton hc l gii cc kt qu ca mnh. Ngoi ra, hu ht cc nh nghin cu ng thi do tin hnh nhiu tnh trng ng thi dn ti cc kt qu ri bi nn khng th nhn ra c cc nguyn l di truyn c s. Mendel tr thnh tu vin trng t nm 1868 v khng cng b thm mt kt qu no v di truyn na k t sau kit tc nm 1866. Mendel qua i nm 1884 trc khi cng trnh ca ng c gii khoa hc thu hiu. Mi n nm 1900, cng trnh ca ng mi c ba nh thc vt hc c lp nhau khm ph li, l Carl Correns ca Germany, Hugo de Vries ca Netherlands v Erich von Tschermak ca Austria. y l mc khi u cho cc nghin cu di truyn hc hin i. Ngy nay, phng php th nghim ca Mendel c xem l th d kinh in v s nghin cu khoa hc c lp k hoch cn thn v bi bo ca ng l s minh ha tuyt vi ca mt thin ti khoa hc.

II. i tng v phng php th nghim ca Mendel

1. i tng

(a) (b) Hnh 1.2 (a) By tnh trng tng phn u H Lan c Mendel nghin cu; dng tri nm bn tri ca mi trng hp. (b) Cu to hoa u, phng php th phn cho v cy u H Lan.

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Mendel chn u H Lan (Pisum sativum) lm i tng nghin cu v chng c hai c im c bn l sai khc nhau v nhiu tnh trng tng phn d quan st (hnh 1.2a) v sinh sn bng li t th phn. Ngoi ra, u c hoa kh ln nn thao tc d dng (hnh 1.2b); c kh nng cho s lng i con nhiu; v nhiu ging u lc by gi c gi tr kinh t cao. 2. Phng php Tnh cht c o ca phng php nghin cu Mendel th hin ch: (1) Chn cc dng thun (pure lines) khc nhau bng cch cho t th phn lin tip nhiu th h dng lm dng b m trong cc php lai; (2) Theo di trc tin kt qu di truyn ring bit ca tng tnh trng qua vi th h, trong th h cy lai th nht hay F1 sinh ra do giao phn gia hai dng b m thun chng khc nhau, cn th h cy lai th hai hay F2 sinh ra t s t th phn ca cc cy lai F1, ri sau mi tin hnh nghin cu s di truyn ng thi ca hai hoc nhiu tnh trng; (3) Khi qut v l gii cc kt qu th nghim thu c bng ton thng k v xc sut; v (4) Kim tra li mt cch cn thn cc gi thuyt khoa hc bng cc php lai thun nghch (reciprocal matings) v lai phn tch (testcross).

III. Lai mt tnh v nguyn l phn ly

1. Kt qu th nghim lai mt tnh (monohybrid cross) Mendel tin hnh by php lai mt tnh khc nhau v cc kt qu thu c c trnh by Bng 1.1.
Bng 1.1 Cc kt qu lai mt tnh ca Mendel F2 TT Kiu hnh P F1 1 Ht trn nhn Trn 5474 trn : 1850 nhn 2 Ht vng xanh Vng 6022 vng : 2001 xanh 3 Hoa ta trng ta 705 ta : 224 trng 4 Qu phng tp Phng 882 phng : 299 tp 5 Qu xanh vng Xanh 428 xanh : 152 vng 6 Hoa dc thn nh Dc thn 651 dc thn : 207 nh 7 Thn cao thp Cao 787 cao : 277 thp T l F2 2,96:1 3,01:1 3,15:1 2,95:1 2,82:1 3,14:1 2,84:1

T tt c cc php lai trn cho thy: Khi b m th h xut pht (P) thun chng khc nhau v mt cp tnh trng tng phn, th th h F1 tt c con lai u biu hin ch mt tnh trng ca b hoc m, tnh trng c gi l tnh trng tri (dominant) v tnh trng kia khng quan st c gi l tnh trng ln (recessive). Sau cho cc con lai F1 t th phn th th h F2 ng thu c c hai kiu hnh (phenotype) ca b m ban u vi t l xp x 3/4 tri v 1/4 ln. Ngoi ra, Mendel cng cho cc cy F2 t th phn ring r v theo di s phn ly th h F3. Kt qu cho thy 1/4 cy ca F2 sinh ra kiu hnh

27

ln tt c u l cc cy ln thun chng; iu c ngha l tt c con ci ca chng l ln. Tuy nhin, trong s 3/4 biu hin kiu hnh tri th mt s l tri thun chng, cn s khc th ging nh cc c th F1 ch chng cho i con gm c tri v ln. Nhn chung, c ba kiu c th F2 l: 1/4 tri thun chng, 1/2 tri khng thun chng (cho i con vi t l 3 tri :1 ln) v 1/4 ln thun chng. 2. Gii thch v kim chng nguyn l phn ly T cc kt qu th nghim Mendel kt lun rng, thng qua cc giao t b m truyn cho con ci cc nhn t di truyn (genetic factor) m ngy nay ta gi l gene. Mendel cn gi rng cc nhn t ny tn ti di vi dng bin i (nay gi l cc allele) xc nh cc kiu hnh khc nhau ca cng mt tnh trng. ng gi nh rng mi c th c hai allele ca mi gene, mt ci nhn t giao t ca b v mt ci t giao t ca m. Mc d iu i vi chng ta by gi c v n gin, nhng thi i Mendel khng c ai hiu c n. By gi ta hy xt th nghim 2. Trc tin, quy c cc gene xc nh cc tnh trng tri v ln bng cc ch ci vit hoa v vit thng, chng hn: A - ht vng, v a - ht xanh. Nh vy c ba kiu gene (genotype), trong hai kiu ng hp t (homozygote) - c hai allele ging nhau: AA v aa, tc dng thun chng v mt kiu d hp t (heterozygote) cha hai alele khc nhau: Aa, tc dng lai. V allele vng l tri hn allele xanh, nn c th d hp t Aa c cng kiu hnh vi th ng hp tri AA. P Ht vng (AA) Ht xanh (aa) Giao t P A a F1 Aa (vng) Giao t F1 ( A : a)ci ( A : a)c Khung Punnett
A A a AA Aa a Aa aa

F2

T l kiu gene 1 AA : 2 Aa : 1 aa T l kiu hnh 3 vng (A-) : 1 xanh (aa)

Hnh 1.3 S biu din kt qu lai mt tnh ca Mendel.

Trong gim phn, mi b m thun chng ht vng (AA) v ht xanh (aa) ch cho mt loi giao t mang allele tng ng l A v a. Do kt qu ca s th tinh ch to ra mt kiu d hp t Aa, ngha l tt c con lai

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F1 u c kiu hnh tri ht vng. Khi bc vo gim phn, cc c th F1 d hp t (Aa) s cho hai loi giao t (A v a) vi t l tng ng. cng l thc cht ca nguyn l phn ly (principle of segregation), hay quy lut th nht ca Mendel (Mendel's first law). Kt qu ca s t th tinh ngu nhin gia cc loi giao t c v ci ca F1 ny s cho ra bn kiu t hp F2, vi t l phn ly theo kiu gene l 1AA: 2Aa: 1aa v t l kiu hnh tng ng l 3 vng (A-): 1 xanh (aa). Lu rng thng thng ngi ta s dng khung Punnett (Punnett square) do nh di truyn hc ngi Anh R.C.Punnett a ra nm 1905 xc nh kt qu di truyn ca cc php lai. S biu din kt qu lai mt tnh c nu hnh 1.3. khng nh nguyn l phn ly, Mendel tin hnh hai th nghim: Mt l, cho cc c th d hp t F1 t th phn nh ni trn; v hai l, cho F1 lai ngc tr li vi b hoc m c kiu hnh ln. Php lai vi mt c th ln nh th c gi l lai phn tch (testcross), thay v gi l lai ngc (backcross) bi v n cho php kim tra kiu gene ca mt c th tri l d hp hay ng hp. C s di truyn ca kiu lai ny nh sau: B m Aa (ht vng) aa (ht xanh) Giao t 50% A : 50% a 100% a i con 50% Aa (vng) : 50% aa (xanh) 3. Nguyn l phn ly v tnh ph bin ca n Sau khi cc nguyn l di truyn ca Mendel c khm ph li nm 1900, tnh ph bin ca cc nguyn l Mendel ni chung v nguyn l phn ly ni ring c cc nh nghin cu khng nh bng cch lp li cc php lai ca ng (chng hn gia u ht vng v ht xanh; bng 1.2) cng nh tin hnh cc php lai tng t cc ng vt v thc vt khc.
Bng 1.2 Cc kt qu lai lp li u H Lan Nh nghin cu Mendel (1866) Correns (1900) Tschermak (1900) Bateson (1905) Darbishire (1909)
Tnh ton b

Vng 6.022 1.394 3.580 11.902 109.060

131.958

Nhn 2.001 453 1.190 3.903 36.186

43.733

T l F2 3,01:1 3,08:1 3,01:1 3,05:1 3,01:1

3,02:1

Ni dung chnh ca nguyn l hay quy lut phn ly c th tm lc nh sau: Cc allele l nhng dng khc nhau ca cng mt gene; trong cc th d hp t chng phn ly v cc giao t vi t l tng ng.

IV. Lai hai tnh v nguyn l phn ly c lp

1. Kt qu th nghim lai hai tnh (dihybrid cross)

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xc nh s di truyn ng thi ca nhiu cp tnh trng, Mendel tin hnh nhiu th nghim khc nhau. Bng 1.3 gii thiu kt qu lai hai tnh gia cc ging u thun chng ht vng-trn v ht xanh-nhn.
Bng 1.3 Cc kt qu lai hai tnh ca Mendel Th h Ptc F1 F2 Kiu hnh ht Vng-trn xanh-nhn Vng-trn Vng-trn Vng-nhn S lng 315 101 108 32
556

Xanh-trn Xanh-nhn
Tng =

T l F2 (quan st) 9,84 3,16 3,38 1,0

T l F2 (k vng) 9 3 3 1

Vi php lai ny, tt c con lai F1 u c kiu hnh tri kp l ht vng v trn. Khi cho F1 t th phn, F2 xut hin 4 kiu hnh l vng-trn, vng-nhn, xanh-trn v xanh-nhn vi t l xp x 9:3:3:1. 2. Gii thch v ni dung nguyn l phn ly c lp Nu xt t l phn ly ca tng tnh trng F2, ta c: 315 + 101 = 416 vng v 108 + 32 = 140 xanh, xp x 3 vng : 1 xanh. Tng t, v hnh dng ht, ta c 315 + 108 = 423 trn v 101 + 32 = 133 nhn, xp x 3 trn : 1 nhn. iu chng t mi tnh trng u tun theo quy lut phn ly 3 tri :1 ln. Bng cch p dng quy tc nhn xc sut ca cc bin c c lp (xem mc VI), ta d dng chng minh c rng s phn ly ca hai t l ny l hon ton c lp nhau nh d on ban u. Tht vy, (3 vng :1 xanh)(3 trn :1nhn) = 9 vng-trn : 3 vng-nhn : 3 xanh-trn : 1 xanh-nhn. Cn lu l t l 9:3:3:1 ny cng c Mendel tm thy trong khi lp li th nghim vi cc tnh trng khc. T ng mi xy dng nn nguyn l phn ly c lp (principle of independent assortment), cn gi l quy lut th hai ca Mendel (Mendel's second law). Ni dung ca nguyn l ny pht biu rng: Cc allele ca cc gene khc nhau th phn ly mt cch c lp vi nhau trong qu trnh hnh thnh giao t (kt qu l to ra t l 9:3:3:1 th h F2 t mt php lai hai tnh). minh ha cho nhng iu trnh by trn y, ta quy c: A - vng, a - xanh, B - trn, b - nhn. Lu : kim tra li gi thuyt phn ly c lp, Mendel tin hnh lai phn tch gia cc cy vng-trn F1 (AaBb) vi cy xanh-nhn (aabb). Kt qu thu c gm 55 vng-trn : 49 vng-nhn : 51 xanh-trn : 53

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xanh-nhn, tng ng vi t l 1:1:1:1 = (1:1)(1:1). iu chng t cc cy F1 cho bn loi giao t vi t l ngang nhau, ngha l cha hai cp gene d hp phn ly c lp. vng, trn xanh, nhn Ptc Kiu hnh Kiu gene AABB aabb Giao t AB ab F1 Kiu gene AaBb Kiu hnh vng, trn Giao t AB : Ab : aB : ab Khung Punnett
AB AB Ab aB ab AABB AABb AaBB AaBb Ab AABb AAbb AaBb Aabb aB AaBB AaBB aaBB aaBb ab AaBb Aabb aaBb aabb

F2

T l kiu gene
1/16 AABB + 2/16 AaBB + 2/16 AABb + 4/16 AaBb 1/16 AAbb + 2/16 Aabb 1/16 aaBB + 2/16 aaBb 1/16 aabb

T l kiu hnh
= 9/16 vng, trn = 3/16 vng, nhn = 3/16 xanh, trn = 1/16 xanh, nhn

Hnh 1.4 C s di truyn hc ca nguyn l phn ly c lp.

V. S di truyn Mendel ngi

Cng nh u H Lan, rui gim hay mo, ngi c rt nhiu tnh trng di truyn theo cc quy lut Mendel. Chng hn, theo thng k ca Victor A.McKusick nm 1994, c 6.678 tnh trng v cc bnh n gene. Cho n ngy 8/2/2005, cc s liu v s lng gene v kiu hnh c nu bng 1.4 (OMIM 2005). Ni chung, vic xc nh phng thc di truyn ngi l tng i kh khn, v mi gia nh c t con, thng khng qu 10 ngi. khc phc iu ngi ta s dng phng php phn tch ph h (pedigree analysis). Di y nu mt s tnh trng tri v ln ngi m khng phn tch c im ca cc kiu di truyn (xem chng 11).

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Bng 1.4 S lng cc mc NST thng 9517 360 1512 1326 2150 14.865 Lin kt X 423 38 137 134 153 885 Lin kt Y 48 0 2 4 2 56 DNA ty th 37 0 27 0 0 64 Tng 10.025 398 1.678 1.464 2.305 15.870

Gene c trnh t bit Gene c trnh t v kiu hnh r M t kiu hnh, c s ph.t r Kiu hnh hay locus Mendel, c s phn t cha bit Cc kiu hnh chnh yu khc c c s Mendel cn kh nghi Tng

1. Cc tnh trng ln (recessive traits) ngi, hu ht cc ri lon di truyn l ln (xem bng 1.5). i a s nhng ngi mc cc bnh ny thng c b m u bnh thng v kiu hnh, nhng li mang gene bnh trng thi d hp.
Bng 1.5 Mt s ri lon n gene thuc nhim sc th thng ngi (phng theo Campbell v Reece 2001; Lewis 2003) Ri lon Cc ri lon ln Bch tng Ha x nang Galactosemia Gaucher Hemochromatosis Phenylketonuria Bnh hng cu lim (ng hp t) Bnh Tay-Sachs Cc ri lon tri Achondroplasia Bnh Alzheimer Bnh Huntington Hypercholesterolemia Khng dung np lactose Hi chng Marfan Cc triu chng (v nguy c mc phi) Thiu sc t da, tc v mt (1/22.000) Tha cht nhy phi, dch tiu ha, gan Tch ly galactose cc m; tr n; tn thng mt v gan. (1/100.000; x l bng king galactose). Gan v lch sng phng, thiu mu, xut huyt ni C th gi li st; nguy c ly nhim cao, tn thng gan, tim v ty , tha sc t da Tch ly phenylalanyl trong mu; thiu sc t da bnh thng; tr n, hn m, cht tui nh (1/10.000) Tn thng lch v nhiu c quan; nguy c ly nhim cao (1/500 ngi M gc chu Phi; ng tri) Tch ly lipid trong cc t bo no gy suy thoi thn kinh; m mu; cht thi th u Ln vi t chi ngn, u v thn bnh thng Thoi ha tm thn; thng xy ra mun mng Thoi ha tm thn v cc c ng mt kim sot Tha cholesterol trong mu; bnh tim; 1/500 l d hp Khng c kh nng phn gii ng lactose, gy ra tnh trng chut rt sau khi n loi ng ny T chi di nh vn, ngc lm, hng thy tinh th, cc ngn tay mnh khnh, ng mch ch suy yu

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Bnh thn a nang Tt nhiu ngn

Cc bng trong cc qu thn, ur trong mu, huyt p cao, au bng di Tha cc ngn tay, ngn chn

Hai bnh ln in hnh l bch tng v ha x nang. Nhng ngi b bch tng (albino) l do thiu ht sc t melanin, nn da d trng bch, tc v trng en ca mt tr nn nht khc thng (hnh 1.5)... Ha x nang (cystic fibrosis) l mt bnh di truyn gy cht ph bin nht M (USA). Bnh ln ny ph bin nht nhng ngi M da trng gc Capca (Caucasians), vi tn s chung l 1/1.800, ngha l trung bnh c 25 ngi c mt ngi mang allele ln ny (Campbell v Reece 2001) hay i vi tr s sinh l 1/2.500 (Weaver v Hedrick 1997). Ngi b bnh ny c c im l tit ra mt lng d tha cht nhy dy phi, ty v cc c quan khc. Cc cht nhy ny c th lm nhiu lon s th, tiu ha v chc nng ca gan v lm cho ngi bnh ri vo nguy c vim phi v cc bnh truyn nhim khc. Nu khng c iu tr, hu ht tr em mc bnh ny s b cht tui ln nm. Theo thng k ca McKusick nm 1994, c 1.730 mc cho cc locus ln. 2. Cc tnh trng tri (dominant traits) Mc d hu ht cc allele c hi l allele ln, nhng mt s cc ri lon ngi l do cc allele tri (xem bng 1.5). Trong s c mt vi allele khng gy cht, chng hn nh tt tha cc ngn tay v chn (hnh 1.5), hoc c mng da gia cc ngn tay v chn. Cc tnh trng nh c tn nhang, di tai thng cng nh cc kh nng un li hnh ng v gp ngc li ln trn u do cc gene tri n khc nhau kim sot. Theo thng k ca McKusick nm 1994, c 4.458 mc cho cc locus tri.

Hnh 1.5 Mt s v d v di truyn Mendel ngi.

T tri sang l bch tng, tt nhiu ngn v dng ln ph bin (achondroplasia).