分子生物學(xué)-mbg-2gene concept基因概念演變與發(fā)展

第2章的概念Concept

of

teTrue-False

QuestionAll

gene

products

are

polypeptides.Answer:

False.

Some

genes

produce

functionalRNAsas

the

terminal

genetic

product

(e.g.,

ribosomal

andtransfer

RNA

genes).經(jīng)典的

概念概念的演變與發(fā)展的分子結(jié)構(gòu)概念的多樣性1866.

-1926.經(jīng)典的概念早期的

概念融合遺傳理論B.C.460

-

370

Hippocrates

（Blending

inheritance）Ancient

Greece

physician

希波克拉底（古希臘名醫(yī)）子代具有父，母雙親的性狀母本體液父本體液+物種加強和完善對環(huán)境的適應(yīng)逐漸轉(zhuǎn)變?yōu)樾路N獲得的性狀是由(非遺傳物質(zhì)的改變)新性狀一旦獲得,便能遺傳給后代獲得性遺傳理論Inheritance

of

acquired

charactersJean-Baptiste

de

Lamarck

1744-1829泛生論假說（Hypothesisof

the

Pangenesis）C.

Darwin

1868Panger種質(zhì)論

(Weismann

老鼠尾巴切割實驗,切割22代,第23代仍有尾巴)（Theory

of

germplasm,Weismann

1883.

）GermplasmRoot,

Stem,

Leaf……→

GermplasmSomatoplasm（體細胞）→

Germplasm

Somatoplasm1834-1914遺傳因子假說(Hypothesis

of

the

inherited

factor

G.J.

Mendel

1866.

)生物性狀由遺傳因子控制親代傳給子代的是遺傳因子(A,a….)遺傳因子在體細胞內(nèi)成雙(AA,aa)在生殖細胞內(nèi)為單（A,a）雜合子體細胞內(nèi)具有成雙的遺傳因子(Aa)等位的遺傳因子獨立分離非等位遺傳因子間

組合地分配到配子中Theoryofte?是

上的實體象鏈珠(bead)一樣，孤立地呈線狀地排列在

上是(Three

in

one)

；功能(functional

unit)突變(mutation

unit)交換(cross-overunit)“三位一體”的最小的不可分割的基本的遺位(1926T.

H.

Morgan)概念的演變與發(fā)展分子生物學(xué)史的第一個重要發(fā)現(xiàn)Onegene

－

OneenzymeThe

one

gene-one

enzyme

hypothesis

is

the

idea

that

genes

actthrough

the

production

of

enzymes,

with

each

gene

responsible

forproducing

a

single

enzyme

that

in

turn

affects

a

single

step

in

ametabolic

pathway.It

is

often

considered

the

significant

result

in

what

came

to

becalled

molecular

biology.

Although

it

has

been

extremely

influential,the

hypothesis

was

recognized

soon

after

its

proposal

to

be

anoversimplification.Even

the

subsequent

reformulation

of

the

"one

gene-onepolypeptide"

hypothesisis

now

considered

too

simple

to

describethe

relationship

between

genes

and

proteins.1941年，GeorgeBeadle和Edward

TatumNeurospora

crassa

（粉色面包霉菌）“one

gene─one

enzyme”的假說（獲得1958年Nobel獎）說明了 的生化作用本質(zhì)是控制酶的生物化學(xué)和遺傳學(xué)之間的聯(lián)合邁出的第一步，也是分子生物學(xué)的第一個重要發(fā)現(xiàn)G.

Beadle&E.

Tatum的位置效應(yīng)PositioneffectＸ－chromosome16ABar

eyePosition

effectDosage

effectDuplicationWild

type780個68個45個Sturtevent385個in

euchromatin常（W>w染色質(zhì)）Ww whiteeye（W

gene

be

silencedin

heterochromatin異染色質(zhì))WWwwWw Red

eyePosition

effectWhy

?Epigenetics

!Epigenetics

表觀遺傳學(xué)Epigenetics

is

the

study

of

heritable

changes

in

phenotype(appearance)

or

gene

expression

caused

by

mechanisms

otherthan

changes

in

the

underlying

DNA

sequence,

hence

the

nameepi-

(Greek:

over,

above)

-genetics.These

changes

may

remain

through

cell

divisions

for

the

remainderof

the

cell's

life

and

may

also

last

for

multiple

generations.

However,there

is

no

change

in

the

underlying

DNA

sequence

of

the

organism;

instead,

non-genetic

factors

cause

the

organism's

genesto

behave

(or

"express

themselves")

differently.擬等位概念的提出（pseudoalleles）Multipleallelesa1Aa2a3Aa1a2a1a1×

a2a2a1a2

(

no

wild

type)野生型

A向不同方向發(fā)生突變形成不同的等位

a1,a2,

a3

….又總稱為復(fù)等位multiple

alleles.But!Ww-wared

eye

(w.t)Xw-Xwa×

Xw-

YXw-

YXw-XwaXw-

Xw-

Xw-

YXw-

Xwa

XwaY?1/1000W.Tred

eyewhiteeye

(mut)amygdaloid

eye

(mut)inDrosophila[?'migd?.l?id]杏仁色Pseudo

Alleles緊密連鎖（交換率極低）功能相同（表型相似）A1

A2a1

a2W.tMut.A1

a2a1

A2(mut)(mut)When

two

mutations

in

the

same

cistron

give

rise

to

differentphenotypes

in

the

cis

and

trans

conditions

respectively,called—(A)Pseudoalleles (B)

Pseudogene(C)Pseudogamy(D)

None

oftheabove(Answer:

A)擬等位

：緊密連鎖，控制同一性狀的非等位pseudo

alleles

是!

?!內(nèi)的突變體.Processed

pseudogenes

arise

from

integration

of

reverse

transcribedmRNAs.

When

reverse

transcriptase

is

present

in

a

cell,

mRNA

molecules

can

be

copied

into

dsDNA.

In

rare

instances,

these

DNA

molecules

canintegrate

into

t ome

creating

pseudogenes.

Because

introns

are

rapidlyremoved

from

newly

transcribed

RNAs,

these

pseudogenes

have

thecommon

characteristic

of

lacking

introns.

This

distinguishes

thepseudogenefrom

the

copy

oft e

fromwhichit

wasderived.

Inaddition,pseudogenes

lack

the

appropriate

promoter

sequences

to

direct

theirtranscription

as

these

are

not

part

of

the

mRNA

from

whichthey

are

derived.PseudogenePseudogenes

are

dysfunctionalrelatives

of

known

genes

thathave

lost

their

protein-codingability

or

are

otherwise

nolonger

expressed

in

the

cell.順反子理論Theory

of

cistron(S.Benzer

1955)對經(jīng)典的 概念的第一次重要修正與發(fā)展1944Oswald

Avery

(Canada)Strptococcum

p

oniceDNA

as

geneticmaterial1941.Beadle

&

TatumNeurospora

crassaOne

gene----one

enzymeJacob

&

Monod1955.

S.BenzerEscherichia

coliLactose

operonE.

coli

T4

phageCistron理論基礎(chǔ)Theory

ofcistronMut.T4

rII

:

rII107,

rII105,

rII51,

rII47……(400)PhageE.coli

BE.coli

k12Seymour

Benzer

1955PlaqueW.t

T4Mut.T4rII白,小,邊緣模糊白,小,邊緣模糊！大,園,邊緣清晰Cis:

Latin:

‘on

this

or

the

near

side

of’.Trans:

Latin:

‘a(chǎn)cross,

beyond,

crossing,

on

the

other

side’.Cistron

and

cis-trans

complementationtestTwo

mutations

in

two

cistrons

and

can

complement

one

another,and

produce

wild-type

phenotype.

A

and

B

represent

two

cistronsor

two

genes./Locked/med

plementation.jpgTwo

mutations

in

the

same

cistron

do

not

complement

oneanother,

and

produce

no

wild-type

phenotype.

A

and

B

representtwo

cistrons

or

two

genes./Locked/med

plementation.jpg順反子假說（Theoryof

cistron）Cistron

是

的同義詞在一個順反子內(nèi)，有若干個突變單位,突變子(muton)在一個順反子內(nèi)，有若干個交換單位,交換子（recon）是一個具有特定功能的，完整的，不可分割的最小的遺

位

three

inone one

in

one內(nèi)可以較低頻率發(fā)生

內(nèi)的重組，交換pseudo

alleles

是mut1

X

mut2內(nèi)的突變體W.t

是內(nèi)發(fā)生交換的結(jié)果概念的動搖cistron概念的提出是對經(jīng)典的是對pseudo

alleles概念的修正等位（Allele,Allomorph）概念的發(fā)展PseudoalleleAllele

同一座位存在的兩個以上不同狀態(tài)的

,

其總和稱之為復(fù)等位 （multiple

alleles）（A,

a1,

a2..）全同等位非全同等位(homoallele)(heteroallele)(非全同等位

)Allele

具有相對差異的DNA區(qū)域TAAAGTAAT

TAAAGCAATGene

locusMut

a1Mut

a2×W.t

AATTCTGAGCTMut

a1ATTCGGAGCTMut

a2ATTCAGAGCTATTCGGAGCTATTCAGAGCT

(mut2)ATTCAGAGCTATTCGGAGCT

(mut1)全同等位

在同一座位(locus)中，同一突變位點（site）向不同方向發(fā)生突變所形成的等位

(

homoallele

)site非全同等位

；在同一

座位（locus）中，不同突變位點（site）發(fā)生突變所形成的等位site。(heteroallele)siteGene

locusMut

a1×Mut

a2W.t

AATTCTGAGCTMut

a1TTCGGAGCTMut

a2ATTCTGAGATATTCGGAGCTATTCGGAGAT

(mut)ATTCTGAGATATTCTGAGCT

(W.t)SummaryBenzer關(guān)于順反子理論的提出不僅將

的

“三位一體”的經(jīng)典概念修正為

的

“一位一體”

概念,

而且動搖或否定了

“擬等位

”

的概念,

認為擬等位

實際上是內(nèi)不同位點的突變體,

是復(fù)等位

的不同成員.同時將

“在同一

座位(locus)中,

同一突變位點向不同方向發(fā)生突變所形成的等位

”

稱為全同等位

(homoallele).將“在同一

座位中,

不同突變位點發(fā)生突變所形成的等位

”稱為非全同等位

(heteroallele).Gene

locusIn

the

diploidcellsof

an

organism,

there

can

be

differentallele(s)

of

a

given

single-copy

nuclear

gene.Only

oneOne

or

twoOne,

two,

three

or

fourManyANSWER:

One

or

twoInapopulation,therecanbe

allele(s)

of

a

given

single-copynuclear

gene.Only

oneOne

or

twoOne,

two,

three

or

fourManyANSWER:

ManyQuestionabcdeThe

diagrams

represent

stages

in

celldivision

bymitosis.

(only

onechromosome

isrepresented).

What

isthe

correct

sequence

of

events?(d)

d

b

a

ce(c)b

a

d

ce(b)

b

a

c

e

d(a)a

b

c

d

eNext

slideeThe

chromosomes

shorten

and

thicken

(b)

after

theyhave

appeared

in

the

nucleus

(b).

Similarly

atofcell

division,

the

chromosomesextend

andless

visible

(d)after

thecell

divides

(e)NoYesThis

isthecorrect

sequenceThe

cell

does

notstart

todivide

(d)

until

thechromatidshave

separated

(c).

Also,

cell

constriction

(e)

precedescell

division

(d)NoNoCell

division

(d)does

not

take

place

until

thechromatidshave

appeared

(b)

and

separated

(c).

Also,

cellconstriction

(e)precedes

cell

division

(d)子理論(Lactose

operon 1961.

Jacob,

Monod)Lac.OperonI

P

O

Z

YAzyaLactose生物體性狀的表現(xiàn)往往具有上位性互作的遺傳效應(yīng)某一是若干功能的表現(xiàn)組成的信息表達的整體行為onegene→ one

peptide（縮氨酸）onegene→onefunction(Ribozyme,Abzyme（抗體酶）,rDNA,tDNA..)one

gene

→oneenzymetDNA,

rDNA,

polymertranscribed,

translatable

gene(

Z,Y,A

)transcribed

but

non-translatablegene(

tDNA,

rDNA,

small

RNA…..

)Non-

transcribed,

non-translatable

gene(

promoter,

operator

)的類型★

cis

action

factor

(表達調(diào)控因子:順式作用因子)Affects

the

activity

only

of

DNA

sequenceson

its

own

molecular

of

DNA,

this

propertyusually

implies

that

the

factor

does

not

codefor

protein通過核苷酸自身的特異二級結(jié)構(gòu)控制與它緊密連鎖的結(jié)構(gòu)

的表達一般不編碼蛋白質(zhì)(無

產(chǎn)物的DNA功能區(qū))★

trans

action

factor

(表達調(diào)控因子：反式作用因子)Affects

the

activity

of

any

gene

located

ongenome

byitstranslated

product.通過擴散自身表達產(chǎn)物（酶，調(diào)節(jié)蛋白）控制其他

的表達可轉(zhuǎn)錄，可翻譯調(diào)節(jié)蛋白的DNA功能區(qū)可通過互補測驗體系確定其功能區(qū)域DNA

is

a

main

genetic

material▲

1928

GriffithRII▲

Hersheylambdar

phage

cycle▲

Watson

&

Crick

DNA

doublehelixDNA1944

Avery

O.TSIIIDNA

是主要的遺傳物質(zhì)DNA編碼兩類遺傳信息phenotype (central

dogma)II類；特定DNA

seq.

+

特定蛋白質(zhì)

/

核酸結(jié)合表達的指令geneon/

offI類；DNA

seq.aaseq.RNA

seq.

(codon)protein內(nèi)在信息ORFonly

expression

byDNA

RNA內(nèi),外(信號分子)結(jié)合信息遺傳信息存在于模版鏈的一級結(jié)構(gòu)上三聯(lián)體簡并(degeneration)WobbleIso-acceptor（同功受體）三(IR,

Box,

paracodon…)空間，調(diào)控

(key

&

lock)cis

1簡并(degeneration)trans1

trans2trans

3cis

1cis

2cis

3I類II類specific

binding結(jié)構(gòu)/DNA序列Helix

,

Ntseq….aa

baseproteinDNA作為遺傳物質(zhì)的優(yōu)點(自然選擇的優(yōu)勢)★

遺傳信息量大1kb

DNA序列

41000

種遺傳信息★

核糖的2’

–

OH

脫氧

在水中的穩(wěn)定性高于RNA★

可以突變方便修復(fù)以求不斷進化以求穩(wěn)定遺傳★

A

/

T,

C

/

G

互補

雙螺旋結(jié)構(gòu),轉(zhuǎn)錄遺傳穩(wěn)定DNA中U潛在的遺傳?G/C

G/UG/C錯配修復(fù)系統(tǒng)傾向除U插CC

U

突變★

DNA中有T無U無后顧之憂DNA擴增進化★DNA中有T無U是進化的結(jié)果錯配修復(fù)系統(tǒng)不能識別兩種U，難以對突變進行修復(fù)的分子結(jié)構(gòu)Nucleic

Acid

(NA)Polynucleotide

chain

(poly

Nt)Nucleotide

(Nt)

basic

unitMono-phosphate

(Mp)Nucleoside

(Ns)Deoxy-ribose脫氧核糖(

Ribose

)BasePurine

(pu)Adenine

(A)Guanine

(G)Pyrimidine

(py)Thymine

(T)Uracil

(U)Cytosine

(C)是DNA分子的片段DNA1.

Double

helixBases(堿基):DNA,adenine(A),guanine(G)

are

purines;cytosine(C),thymine(T)

arepyrimidinesRNA,

…… uracil

(U)…Nucleosides:

base

+

sugar

=

nucleosideNucleotides:

base

+

sugar

+

phosphate

=

nucleotides(

核苷酸

)

The

nucleoside

5’-triphosphates

(NTPs

or

dNTPs)

arerespectively

the

building

blocks

of

polymeric

RNA

and

DNAPhosphodiester

bonds:

covalent

linkage

of

a

phosphate

group

between

the(磷酸二脂鍵)

5’-hydroxyl

ofariboseand

the

3’-hydroxylof

thenext.

At

neutral

pH,

each

phosphate

group

has

a

single

negative

charge.Nucleic

acids

are

thus

highly

charged

polymers.(核苷)RNA:

ribonucleosides

or

just

nucleosides;DNA:

2’-deoxyribonucleosidesorjustdeoxynucleosidesDNA/RNA

sequence:

The

nucleic

acid

sequence

is

the

sequence

ofbasesA,

C,

G,

T/U

in

the

DNA/RNA

chain.

The

sequence

isconventionally

written

from

the

free

5’-

to

the

free

3’-

endofthemolecule,5’-

ATTAGCTC-

3’(DNA)

, 5’-

AUAGCUUGA-3’

(RNA)DNA

double

helixDNA是右手螺旋(right-handed

double

helix)。雙螺旋包括兩條多核苷酸鏈.磷酸-核糖骨架(back-bone)在外側(cè)，含氮堿基層狀排列在雙螺旋

。兩條多核苷酸鏈的堿基通過氫鍵(hydrogen

bonding)互作。雙螺旋每一圈有10個堿基對(basepairs)，長度為34

Angstroms，螺旋的直徑20

Angstroms

。雙螺旋的兩條鏈是反向平行互補的

(anti-parallel

and

complementary)。雙螺旋有兩種不同的溝:major

grooves

and

minor

grooves。Major

grooves:

the

place

for

gene

expression

regulation.Nucleotide

(Nt)

basic

unitA

portion

of

a

DNApolynucleotide

chain,showing

the

3'

→

5'phosphodiester

linkagesthat

connect

thenucleotides.

Phosphategroups

connect

the

3'carbon

of

one

nucleotidewith

the

5'

carbon

of

thenext.The

nucleotidesof

DNA.

Thestructures

of

thedifferentcomponents

ofeach

of

the

fournucleotides

areshown.A

portion

of

apolyribonucleotide(RNA)

chain.Elements

in

redare

distinct

fromDNA.Distinctions

between

the

nucleotides

of

RNA

and

DNA.

A

nucleotide

of

DNAis

shown

next

to

a

nucleotide

of

RNA.

All

RNA

nucleotides

have

the

sugarribose

(instead

of

deoxyribose

for

DNA),

which

has

a

hydroxyl

group

oncarbon

2

(shown

in

red).

In

addition,

RNA

has

the

pyrimidine

base

uracilinstead

of

thymine.

The

three

other

bases

that

occur

in

DNA

and

RNA

areidentical.Which

of

the

following

is

a

true

statement

regardingmessenger

RNA

(mRNA)?

mRNA

is

single

stranded

while

DNA

is

doublestranded.

mRNA

uses

a

uracil

nucleotide

instead

ofthyminebut

all

other

nucleotides

are

used

by

both

nucleicacid

species.

RNA

nucleotides

use

a

ribose

sugar

while

DNAnucleotides

use

a

deoxyribosesugar.all

of

the

aboveAnswer:

D核苷的構(gòu)象(conformationof

nucleoside)χ =

C4-N9---C1’-O4’0opurinepyrimidineχ =

C2-N1---C1’-O4’0oDNA

雙螺旋結(jié)構(gòu)模型(DNA

Double

Helix

Model)1938.

W.

T.

AstburyX~

ray

photograph

of

DNA1950.

Erwin

ChargaffA

+G

/

T

+C

=

1A+T

= G+CRich

AT

form

&

rich

GC

form1952. Alexander

Todd3’,

5’

phosphodiester

bondNt~~Nt~~Nt~~Nt~~Nt1953. Watson

&

CrickRight

handed

B-form

DNADouble

helix

Model堿基的重疊與堆積G-C

pair,

held

together

by

three

hydrogen

bondsA-T

pair

,held

together

by

two

hydrogen

bonds162342The

hydrogen-bondedbase

pairs

of

DNA.The

figure

shows

theposition

and

length

ofthe

hydrogen

bondsbetween

the

base

pairs.The

covalent

bondsbetween

the

atomswithin

each

base

areshown,

but

double

andsingle

bonds

are

notdistinguished.QuestionIn

a

DNA

molecule,

whichof

the

molecules

listedbelo irs

with

adenine?thymineguaninevalinecytosineNext

slidethymineYesadenineNoguaninecytosineGuanine

pairs

with

cytosineNoValine

is

an

amino

acid

and

not

an

organicbaseNocytosineguanineCytosine

pairs

with

guaninel

堿基頂部基團 露在DNA

大溝內(nèi)l

蛋白質(zhì)因子與DNA

的特異結(jié)合依賴于氨基酸與DNA

間的氫鍵的形成l

蛋白質(zhì)因子沿大溝與DNA形成專一性結(jié)合的機率與多樣性高于沿小溝的結(jié)合l

大溝的空間更有利于與蛋白質(zhì)的結(jié)合DNA雙螺旋的結(jié)構(gòu)特點The

helical

structure

of

DNA.

(a)

Schematic

model

of

the

double

helix.

One

turn

ofthe

helix

(3.4

nm)

spans

approxima y

10.5

base

pairs,

(b)

Space-filling

model

ofthe

double

helix.

The

sugar

and

phosphate

residues

in

each

strand

form

thebackbone,

which

are

traced

by

the

yellow,

gray,

and

red

circles,

showing

the

helicaltwist

of

the

overall

molecule.

The

bases

project

inward

but

are

accessible

throughmajor

and

minor

grooves.Formation

of

nucleotide

by

removal

of

water.

The

numbers

of

thecarbon

atoms

in

2'-deoxyribose

are

labeled

inred.Right

handed

B-form

DNADouble

helix

Model每一單鏈具有5‘

3’

極性兩條單鏈間以氫鍵連接兩條單鏈，極性相反，反向平行以中心為軸，向右盤旋(B-form)雙螺旋中存在大溝(2.

2nm)小溝(1.

2nm)影響雙螺旋結(jié)構(gòu)穩(wěn)定性的因素堿基堆積的棒狀實體氫鍵

(Hydrogen

bond 4~6

kc

/mol)弱鍵,可加熱解鏈氫鍵堆積,有序排列(線性,方向)磷酸酯鍵(phosphodiester

bond

80~90kc/mol)強鍵,需酶促解鏈0.2

mol/L

Na+生理鹽條件消除DNA單鏈上磷酸基團間的靜電斥力l

堿基堆積力(非特異性結(jié)合力)3.4A°(0.34

nm/堿基對間距)(1

kc/mol—0.6kc/mol)×n(熱運動消耗)☆磷酸骨架,氨基,酮基周圍水分子間的有序排列☆

Van

de

waals

force

(1.7A°/嘌呤環(huán)與嘧啶環(huán)作用半徑)☆疏水作用力(Hydrophobic

interaction)不溶于水的非極性分子在水中相互聯(lián)合,成串結(jié)合的疏水作用力，即為熵Entropy

（ΔS）DNA分子中非極性堿基的

, ,產(chǎn)生疏水作用力成為堿基間的部分堆積力磷酸基團間的靜電斥力堿基間的擠壓、抵御使其內(nèi)能增加,堿基間有序排列的狀態(tài)破壞（氫鍵作用力被減弱）影響雙螺旋結(jié)構(gòu)穩(wěn)定性的因素氫鍵

(Hydrogen

bond 4~6

kc

/mol)磷酸酯鍵

(phosphodiester

bond 80~90

kc

/mol)0.2mol/L Na+生理鹽條件堿基堆積力(非特異性結(jié)合力)磷酸基團間的靜電斥力堿基間的擠壓、抵御使其內(nèi)能增加,堿基間有序排列的狀態(tài)破壞（氫鍵作用力被減弱）DNA分子變性(DNA

denaturation)D.S.

DNA(加溫,S.S.

DNApH,尿素,酰胺)變性過程的表現(xiàn)☆S.S.

DNA粘度降低D.S

DNAS.S

DNA粘度降低？溶液粘度取決于分子流動過程中的內(nèi)摩擦和阻力高分子溶液

>普通溶液線狀分子>

不規(guī)則線團

>

球形分子D.S.DNA

鋼性較強，結(jié)構(gòu)較為舒展的Double

helixS.S.DNA

沒有