Мутагенез при интеграционных процессах и эволюция ядерного генома
Рассмотрены вопросы мутационной изменчивости, вызываемой крупными структурными перестройками генетического материала, такими как транспозиции мобильных генетических элементов, интеграция или дезинтеграция экзогенных нуклеотидных последовательностей вирусной и невирусной природы, изменения хромосомно...
Збережено в:
| Опубліковано в: : | Біополімери і клітина |
|---|---|
| Дата: | 2007 |
| Автор: | |
| Формат: | Стаття |
| Мова: | Russian |
| Опубліковано: |
Інститут молекулярної біології і генетики НАН України
2007
|
| Онлайн доступ: | https://nasplib.isofts.kiev.ua/handle/123456789/157526 |
| Теги: |
Додати тег
Немає тегів, Будьте першим, хто поставить тег для цього запису!
|
| Назва журналу: | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| Цитувати: | Мутагенез при интеграционных процессах и эволюция ядерного генома / Л.Л. Лукаш // Біополімери і клітина. — 2007. — Т. 23, № 3. — С. 172-187. — Бібліогр.: 43 назв. — рос., англ. |
Репозитарії
Digital Library of Periodicals of National Academy of Sciences of Ukraine| id |
nasplib_isofts_kiev_ua-123456789-157526 |
|---|---|
| record_format |
dspace |
| spelling |
Лукаш, Л.Л. 2019-06-20T04:21:11Z 2019-06-20T04:21:11Z 2007 Мутагенез при интеграционных процессах и эволюция ядерного генома / Л.Л. Лукаш // Біополімери і клітина. — 2007. — Т. 23, № 3. — С. 172-187. — Бібліогр.: 43 назв. — рос., англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000764 https://nasplib.isofts.kiev.ua/handle/123456789/157526 577.21+575.857 Рассмотрены вопросы мутационной изменчивости, вызываемой крупными структурными перестройками генетического материала, такими как транспозиции мобильных генетических элементов, интеграция или дезинтеграция экзогенных нуклеотидных последовательностей вирусной и невирусной природы, изменения хромосомного набора или отдельных хромосом, диминуция хроматина, и роль такой изменчивости в эволюции ядерного генома. Mutational variability induced by large-scale reorganizations of genetic material such as MGE transpositions, integration or disintegration of exogenous nucleotide sequences of viral and non-viral origin, changes in chromosome set or individual chromosomes, chromatin diminution and its role in the evolution of nuclear genome are discussed. Розглянуто питання мутаційної мінливості, спричиненої великими структурними перебудовами генетичного матеріалу, такими як транспозиції мобільних генетичних елементів, інтеграція або дезінтеграція екзогенних нуклеотидних послідовностей вірусної та невірусної природи, зміни хромосомного набору або окремих хромосом, димінуція хроматину, і роль такої мінливості в еволюції ядерного геному. ru Інститут молекулярної біології і генетики НАН України Біополімери і клітина Мутагенез при интеграционных процессах и эволюция ядерного генома Мутагенез при інтеграційних процесах і еволюція ядерного геному Mutagenesis induced by integration processes and evolution of nuclear genome Article published earlier |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| title |
Мутагенез при интеграционных процессах и эволюция ядерного генома |
| spellingShingle |
Мутагенез при интеграционных процессах и эволюция ядерного генома Лукаш, Л.Л. |
| title_short |
Мутагенез при интеграционных процессах и эволюция ядерного генома |
| title_full |
Мутагенез при интеграционных процессах и эволюция ядерного генома |
| title_fullStr |
Мутагенез при интеграционных процессах и эволюция ядерного генома |
| title_full_unstemmed |
Мутагенез при интеграционных процессах и эволюция ядерного генома |
| title_sort |
мутагенез при интеграционных процессах и эволюция ядерного генома |
| author |
Лукаш, Л.Л. |
| author_facet |
Лукаш, Л.Л. |
| publishDate |
2007 |
| language |
Russian |
| container_title |
Біополімери і клітина |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| format |
Article |
| title_alt |
Мутагенез при інтеграційних процесах і еволюція ядерного геному Mutagenesis induced by integration processes and evolution of nuclear genome |
| description |
Рассмотрены вопросы мутационной изменчивости, вызываемой крупными структурными перестройками генетического материала, такими как транспозиции мобильных генетических элементов, интеграция или дезинтеграция экзогенных нуклеотидных последовательностей вирусной и невирусной природы, изменения хромосомного набора или отдельных хромосом, диминуция хроматина, и роль такой изменчивости в эволюции ядерного генома.
Mutational variability induced by large-scale reorganizations of genetic material such as MGE transpositions, integration or disintegration of exogenous nucleotide sequences of viral and non-viral origin, changes in chromosome set or individual chromosomes, chromatin diminution and its role in the evolution of nuclear genome are discussed.
Розглянуто питання мутаційної мінливості, спричиненої великими структурними перебудовами генетичного матеріалу, такими як транспозиції мобільних генетичних елементів, інтеграція або дезінтеграція екзогенних нуклеотидних послідовностей вірусної та невірусної природи, зміни хромосомного набору або окремих хромосом, димінуція хроматину, і роль такої мінливості в еволюції ядерного геному.
|
| issn |
0233-7657 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/157526 |
| citation_txt |
Мутагенез при интеграционных процессах и эволюция ядерного генома / Л.Л. Лукаш // Біополімери і клітина. — 2007. — Т. 23, № 3. — С. 172-187. — Бібліогр.: 43 назв. — рос., англ. |
| work_keys_str_mv |
AT lukašll mutagenezpriintegracionnyhprocessahiévolûciââdernogogenoma AT lukašll mutagenezpriíntegracíinihprocesahíevolûcíââdernogogenomu AT lukašll mutagenesisinducedbyintegrationprocessesandevolutionofnucleargenome |
| first_indexed |
2025-11-24T21:48:08Z |
| last_indexed |
2025-11-24T21:48:08Z |
| _version_ |
1850498571897405440 |
| fulltext |
Mutagenesis in duced by in te gra tion pro cesses and
evo lu tion of nu clear ge nome
L. L. Lukash
The In sti tute of Mo lec u lar Bi ol ogy and Ge net ics
150 Zabolotny Str., Kyiv 03143, Ukraine
imbig@serge.relc.com
Mutational vari abil ity in duced by large-scale re or ga ni za tions of ge netic ma te rial such as MGE trans po si -
tions, in te gra tion or dis in te gra tion of ex og e nous nu cle o tide se quences of vi ral and non-vi ral or i gin,
changes in chro mo some set or in di vid ual chro mo somes, chromatin dim i nu tion and its role in the evo lu tion
of nu clear ge nome are dis cussed.
Key words: mu ta gen e sis, chro mo some, chromatin dim i nu tion
Now a days, the ques tion of mu ta gen e sis are brought
for ward among the ma jor ity of sci en tific in ves ti ga tions
due to the fact that anthropogenic pol lu tion of the en vi -
ron ment lead to in ten sive ac cu mu la tion of mu ta tions in
hu man ge nome, which is out of the con trol of nat u ral
se lec tion. Some fore casts say that it may af fect es sen -
tially the num bers of in her ited and so matic dis eases,
life time du ra tion, and pos si ble prog eny. Ge netic in sta -
bil ity, in duced by fac tors of dif fer ent or i gin, is con sid -
ered to be the main mech a nism in the com plex
multi-staged pro cess of ma lig nant ret ro gres sion of hu -
man so matic cells [1].
The use of ge net i cally mod i fied prod ucts in ev ery -
day life and re com bi nant DNAs in cluded as parts of vi -
ral vec tors as novel phar ma co log i cal gene ther a peu tic
prep a ra tions [2] un veiled the prob lem of ge netic con se -
quences of the in tro duc tion of allogenic bi o log i cal fac -
tors into the hu man or gan ism.
Mu ta tions as in her ited changes of ge netic ma te -
rial. The ca pac ity to change ge netic ma te rial – to mu -
tate – is the uni ver sal ca pa bil ity of the liv ing be ings –
from vi ruses and mi cro or gan isms to higher plants, an i -
mals, and hu mans. Mutational vari abil ity is the ge netic
vari abil ity which in volves changes in ge no type as a re -
sult of mu ta tions. The dis or ders oc curred may af fect
the nu cle o tide se quences in a DNA mol e cule, cause re -
ar range ments of chro mo somes, and re sult in in crease or
de crease in num bers of some chro mo somes or sets of
chro mo somes. The most com mon def i ni tion of the no -
tion of mu ta tion was pro vided by Zhimulev in his book
Gen eral and Mo lec u lar Ge net ics – “mutational vari -
abil ity is the in her ited change ability of ge netic ma te -
rial” [3].
Many prin ci ples have been ap plied to clas sify mu -
ta tions. Usu ally, the mu ta tions are clas si fied not in
their phenotypic man i fes ta tions but in the pat tern of
changes in ge netic ap pa ra tus. Inge-Vechtomov sin gled
out three types of mu ta tions as fol lows: i) ge netic or
172
ISSN 0233-7657. Biopolymers and cell. 2007. Vol. 23. ISS 3. Translated from Ukrainian.
ã L. L. LUKASH, 2007
MUTAGENESIS IN DUCED BY IN TE GRA TION PRO CESSES
point mu ta tions, ii) changes in the struc ture of chro mo -
somes or chro mo somal re ar range ments, iii) changes in the
sets of chro mo somes [4]. Gershenson’s monography pres -
ents mu ta tions in four ba sic groups: i) changes in the sets
of chro mo somes (or genomic mu ta tions), ii) changes in
num bers of some chro mo somes (aneuploidy), chro mo -
somal re ar range ments (chro mo somal ab er ra tions), iv) ge -
netic (point) mu ta tions [5, 6]. Many au thors still ad here to
these clas si fi ca tions, though these clas si fi ca tions had to be
re vised long time ago due to the es sen tial en rich ment of
the ideas on mu ta tions with the new and sig nif i cant data
[3].
Cer tain level of ge netic sta bil ity is “en coded” into the
struc ture of the cell ge nome and is de pend ent on the work
of mutator and anti-mutator genes, var i ous reg u la tory ge -
netic el e ments, re spon si ble for the ba sic pro cesses in the
ma trix, i.e. rep li ca tion, re com bi na tion, rep a ra tion, mod i fi -
ca tion, and re stric tion [7–10]. As a rule, spon ta ne ous mu -
ta tion in prokaryotic and eukaryotic or gan isms is spe cific
for its low fre quency (10–5–10–8), ow ing to the ef fec tive
work of en zymes with corrector and re par a tive func tions,
and is hereditarily fixed fea ture. Zhestyannikov in his
book DNA Rep a ra tion and its Bi o log i cal Sig nif i cance
states that the value, in versely pro por tional to the fre -
quency of spon ta ne ous mu ta tions, ap par ently, char ac ter -
ises the level of ge netic sta bil ity of a biosystem [7].
As the mu ta tions are con sid ered to be the source
of ge netic vari abil ity of the pop u la tion, there has
been rel a tively con stant rate of spon ta ne ous mu ta -
tions, spe cific to a cer tain ge nus or type of the cells,
se cured evolutionarily as the nec es sary con di tion of
growth and ad ap ta tion [11]. This ge net i cally se -
cured fea ture has been main tained at the cer tain level
by the sys tems of pro tec tion of the or gan ism. For in -
stance, the for ma tion of anti-body-form ing cells, ge -
netic in sta bil ity is main tained at the same level
through out the or gan ism life time, yet it is strictly re -
stricted by some re gions of cor re spond ing genes.
The ap pli ca tion of nat u ral genomes (e.g.
onco-vi ruses) along with the de vel op ment of gene
en gi neer ing method of DNA-con struc tions made it
pos si ble to in flu ence the mu ta tion rate in cell pop u -
la tions [12]. All facts pre sented al low stat ing that
the pos si bil ity of reg u la tion of mutational vari abil ity
at the level of cell as well as at the level of or gani sa -
tion of the liv ing.
The chief spec i fic ity of eukaryotic ge netic ma te -
rial, com par ing to the prokaryotic one, is the pres -
ence of sur plus DNA and some nu cle o tide se quences
of dif fer ent re peat abil ity in heterochromatin re gions
[13]. Heterochromatin re gions pos sess the se ries of
fea tures, which make them dif fer ent euchromatin
173
Fig.1 Sys tem of two types of in ter change of nu cle o tide se quences of dif fer ent re peat abil ity [13]
ones. The rel a tive com pact ing con stancy and ca pa bil -
ity to con ju ga tion are among the main ones. The ideas
on the sig nif i cant role of heterochromatin re gions in the
ge nome evo lu tion are com monly known [3].
Fig. 1 pres ents the scheme of two types of in ter -
change of nu cle o tide se quences of dif fer ent re peat abil -
ity. The par a doxes of eukaryotic genomes can be
listed: i) dis agree ment of ge nome sizes and lo ca tion of
spe cies on the evo lu tion ary step-lad der, ii) sig nif i cant
dif fer ences in the sizes of ge nome and the con tents of
sur plus DNA in closely re lated spe cies, liv ing in the
same con di tions. The lat ter tes ti fies in fa vour of the
fact that the ge nome size of closely re lated or i gin-wise
spe cies re mained in con stant through out the evo lu tion.
How is it then that their genomes be came big ger and/or
smaller so fast?
Many dif fer ent hy poth e ses have been stated re gard -
ing the role of sur plus DNA, the com par a tive anal y sis
of which brought up the con clu sion that sur plus DNA
per forms nei ther en cod ing nor reg u la tory func tion. For
some time sur plus DNA was called ego is tic, par a sitic,
and even junk, till the mo ment its pos si ble role in evo lu -
tion of genomes be gan to un veil. This kind of sup po si -
tion was put for ward by Akifjev more than 30 years ago
[14].
To the au thor’s opin ion, the idea of sur plus DNA as
“evo lu tion ary melt ing pot”, where new struc tural genes
and the reg u la tory se quences are ma tured, as it has been
pro posed by Swed ish bi ol o gists Edström, seems to be
the most ap pro pri ate. Some of the ideas on this is sue
have been pro posed by Rus sian ge net i cist Serebrovsky
in 1920’s. It is se verely doubted that the new gene
could be formed at the ex pense of mutational re ar range -
ment of the old one if the lat ter is pre sented by a sin gu -
lar copy. In case when there is the sur plus of ge netic
ma te rial in the form of dou bled (du pli cated) genes, then
one of them may not func tion. With the pe riod of time
this “si lent” gene ac cu mu lates gene mu ta tions, hav ing
changed it so much that this gene pres ents it self a new
struc tural or reg u la tory gene. At these con di tions this
gene may start func tion ing, form ing a new pro tein
prod uct and, con se quently, new fea ture. Yet this pro -
cess is very slow, which can not be ex plained by fast
change in ge nome evo lu tion.
There fore, hav ing un der es ti mat ing not the role of
ge netic mu ta tions and chro mo somal ab er ra tions, we
have de cided to fo cus on mu ta tions, oc cur ring in the
course of large struc tural re or gani sa tions of ge nome, as
they may be of spe cial value for ac cel er ated evo lu tion.
Pri mar ily, these large struc tural re ar range ments in -
clude:
a.) in ser tions and de le tions of nu cle o tide se -
quences at the in te gra tion of mo bile ge netic el e ments
(MGE), vi ruses, which trans form the DNA;
b.) macromutations – changes in the num ber
of sets of chro mo somes, ap pear ance and elim i na tion of
some chro mo somes, chro mo somal re ar range ments,
chromatin dim i nu tion (the loss of ge netic ma te rial dur -
ing the for ma tion of so matic cells out of germ cell
lines).
Thus, cur rent pa per will pres ent the dis cus sion on
mutational vari abil ity, oc cur ring dur ing large struc tural
re ar range ments of ge netic ma te rial, such as MGE trans -
po si tions, in te gra tions and dis in te gra tions of exo gen ic
nu cle o tide se quences of vi ral and non-vi ral or i gin, the
changes on the level the whole chro mo somal ap pa ra tus
and sep a rate chro mo somes, chromatin dim i nu tion, and
the role of this vari abil ity in the evo lu tion of nu clear ge -
nome. There will be some ex am ples of evo lu tion of cell
genomes con nected with in cor po ra tion of adenovirus
DNA, exo gen ic trans form ing DNA, changes in sets of
ba sic and ad di tional chro mo somes in some an i mal spe -
cies and the loss of ge netic ma te rial pres ent in germ line
cells.
MGE sys tems as fac tors and ob jects of evo lu -
tion. The com par i son of frag ments of exo gen ic DNA,
in tro duced into the cell by var i ous meth ods, with MGE,
dis cov ered by McClintock in 1956 and in ves ti gated in -
ten sively ever since, is con sid ered to be rea son able [3].
Hersin con sid ered al most any nu cle o tide se quence, sur -
rounded by DNA re peats, ca pa ble of be com ing a mo -
bile el e ment [8]. At the same time it has to be noted that
dif fer ent MGE types may be con trib uted by exo gen ic
DNA into the cell sys tem, as well as they can be ac ti -
vated in cell ge nome as a re sult of transfection and
genomic stress [15–17].
Among the bi o log i cal fac tors, ca pa ble of de sta bi lis -
ing cell ge nome, MGE and oncogenic vi ruses are dis -
tin guished the most. MGE re lo ca tions ev i dently play
the im por tant role in both the pro cess of nor mal de vel -
op ment and the dif fer en ti a tion of stem cells into the
spe cial ized ones and in ma lig nant trans for ma tion of tis -
LUKASH L. L.
174
sues [15]. Not in vain the onco genes are some times
called “mo lec u lar ro bots”, ca pa ble of de sta bi lis ing the
cell ge nome and chang ing the programme of cell ge -
nome to wards the ma lig nant trans for ma tion.
No ta bly, bi o log i cal fac tors of reg u la tory ef fect on
mu ta gen e sis also in clude nu cleic ac ids, hor mones, reg -
u la tory and en zy matic func tions, vi ta mins, and var i ous
cell me tab o lites [18]. Both MGE and vi ruses in flu ence
the mu ta gen e sis via the ex pres sion of genes of their
own and the ac ti vated cell genes [19]. How ever, this ar -
ti cle deals with the other as pect of the in flu ence on the
mutagenic pro cess and evo lu tion, namely, the con se -
quences of the in te gra tion of exo gen ic nu cle o tide se -
quences into cell DNA.
In ser tions of MGE into the en cod ing zones of genes
re sult in dis or der ing or rapid change in their func tions,
due to the di rect dam ag ing of en cod ing nu cle o tide se -
quence of genes and the in flu ence of punc tu ators (pro -
mot ers, ter mi na tors, enhancers) on read ing-in pro -
cesses. The mu ta tions are es pe cially nu mer ous in
prokaryotes of high den sity of en cod ing se quences in
ge nome [16, 17].
Mean while, in the genomes of higher eukaryotes,
where en cod ing se quences are as nu mer ous as is lands
in the ocean (3–5%), MGE are most com monly in cor -
po rated into the nu cle o tide se quences of sur plus DNA
[15–17]. In ser tions of MGE into non-en cod ing ar eas
(spac ers, introns, flank re gions, etc.) re sult in lighter
con se quences – in ten si fi ca tion or de cay ing in ac tiv ity
of neigh bour ing genes, changes in their reg u la tion.
How ever, the ap pear ance of an ad di tional MGE-be -
long ing enhancer, in the close prox im ity to func tional
cell gene, is ca pa ble of ac ti vat ing this gene rap idly. The
enhancers can in crease the level of tran scrip tion of the
neigh bour ing genes, at the dis tance up to 5 000 b.p., in
ten and hun dred times.
MGE lo cal isa tion pat tern for ev ery case is rel a -
tively sta ble and the sites, avail able for in ser tion, are,
ev i dently, “re mem bered by mo lec u lar mem ory” for a
long time [17]. It may be con sid ered as the sig nif i cant
com po nent of the mech a nism of de ter mi na tion of quan -
ti ta tive fea tures. Gen er ally, these sys tems con tain the
fol low ing: 1.) oligogenes (the genes of main ef fect),
nec es sary for the for ma tion of the fea ture; 2.)
polygenes, each of them is not a nec es sary com po nent
of the for ma tion of the fea ture, yet to gether they are ca -
pa ble of al ter ing its ex pres sion; 3.) MGE, mod i fy ing
and in ten si fy ing the ac tiv ity of the nearby oligogenes
and polygenes.
Crit i cal stress con di tions of ex is tence are of ten con -
nected with the pop u la tion’s beat ing through “the bot -
tle-neck stage”, which may re sult in ei ther mas sive ex -
tinc tion or ad ap ta tion to new eco log i cal niches ac cord -
ing to the founder’s prin ci ple [16, 17]. MGE are
con sid ered as spe cific re cep tors of stress sig nals from
in ter nal or ex ter nal en vi ron ment, which also start sys -
temic out breaks of ge netic vari abil ity, up to the es tab -
lish ment of new ge netic ho meo sta sis in the crit i cal pe ri -
ods of evo lu tion of the pop u la tions. The forms, in -
duced at these con di tions, may be the found ers of new
pop u la tions with dis tinc tively changed phe no type in
ac cor dance with lim ited quan ti ta tive or qual i ta tive fea -
tures. It is not ex cluded, how ever, that the changes in
MGE lo cal isa tion pat terns are one of the mech a nisms
of the for ma tion of spe cies.
Gene and func tional sites of retroposons are sub -
jected to the in ten sive mu ta gen e sis, as their ge netic ma -
te rial goes through the RNA-stage in the course of rep -
li ca tion, mu ta tion pos si bil ity at this stage is 10–3–10–4,
which is ten, hun dreds times higher than the pos si bil ity
of mu ta tion of genes in the eukaryotic DNA.
MGE sys tems are spe cific for the fol low ing func -
tions:
serve the source of insertional vari abil ity of
genes;
in flu ence the ap pear ance of quan ti ta tive
and qual i ta tive fea tures;
re sponse to ex ter nal stresses, tem per a ture
fluc tu a tions, in creases of transpositional vari abil ity;
re sponse for the changes of lo cal isa tion pat -
terns of nu mer ous MGE at the same time dur ing the se -
lec tion ac cord ing to some fea tures.
To some ex tent, these fea tures are spe cific to MGE
of dif fer ent ob jects, namely, yeasts, drosophilae, plants,
mam mals. Mu ta tions may oc cur not only in sites of in -
cor po ra tion of MGE un der the in flu ence of trans po si -
tion-pro vid ing en zymes in instable cell sys tems but
also in many other loci [8].
Evo lu tion of cell ge netic ma te rial dur ing the in -
te gra tion of vi ruses and DNA trans for ma tions.
Genomes of oncogenic vi ruses, es pe cially DNA-con -
tain ing ones, are much more com pli cated or gani sa -
MUTAGENESIS IN DUCED BY IN TE GRA TION PRO CESSES
175
tion-wise than genomes of MGE. Fig. 2 pres ents the re -
stric tion card of ge nome of a typ i cal adenovirus (bo vine
adenovirus, type 3). Ge nome of adenovirus is rep re -
sented by a lin ear DNA mol e cule with long di rect re -
peats at the ends. Operons E1A and E1B, com pris ing
the trans for ma tion re gions, re spon si ble for ma lig nant
trans for ma tion of cells, are local ised on the left end of
ge nome, the right end lo cates the early E4 re gion,
which con trols the pro cess of trans for ma tion proper.
The anal y sis of the in te gra tion of this one and some
other DNA-con tain ing vi ruses into the chro mo somal
DNA re vealed sev eral stages of es tab lish ing of the in te -
grated state and ma lig nant trans for ma tion of cells
[20–24]. The main stages can be pre sented as fol lows:
es tab lish ment of in te grated state and man i -
fes ta tion of struc tural in sta bil ity;
sta ble trans for ma tion, last ing for ten and
hun dreds of cell gen er a tions;
in ac ti va tion of nu cle o tide se quences as a re -
sult of methylation and their con se quent elim i na tion.
The math e mat i cal mod el ling of man i fes ta tion of
mu ta gen e sis in the sys tem of adenovirus-cell re vealed
two in ten sive in creases in fre quen cies of mu ta tions –
the first peak, manifestated mod er ately, co in cides with
the pe riod of tem po rary ex pres sion; the sec ond one co -
in cides with the pe riod of struc tural in sta bil ity at the es -
tab lish ment of in te grated state (Fig. 3) [25]. Fig.4 pres -
ents the se ries of the in ves ti gated events in
adenovirus-cell sys tem in time.
The re sult ing mutagenic ef fect of exo gen ic
mutagen is de ter mined by both the in ter ac tion in ten sity,
the pos si bil i ties of mech a nisms of pro tec tion of the cell,
LUKASH L. L.
176
Fig.2 Re stric tion card of BAV3 ge nome
the specificities of intercellular en vi ron ment, and the
me tab o lism. Ev i dently, grad ual de crease in the fre -
quen cies of the in duced mu tants in cell pop u la tions in
time (Fig.3) re flects the dy nam ics of mutagen re moval
of the cell and the ef fect of re par a tive as well as some
other mech a nisms of pro tec tion.
Free vi rus DNAs are fast to ar range and dis ar range
[21], which, ap par ently, de ter mines the short-last ing
time of early mutagenic ef fect. Func tional in ac ti va tion
(as a re sult of methylation) and re moval of the in cor po -
rated exo gen ic DNA mol e cules take more time and
mainly de ter mined by their struc tural and func tional
specificities and re par a tive ca pa bil i ties of cell sys tems
[22]. The in crease in the level of in duced mu ta tions
long af ter transfection (4–7 weeks), ev i dently, re flect
the dy nam ics of in ac ti va tion and re moval of vi ral nu -
cle o tide se quences and the death of mu ta ble cells,
“over loaded” with mu ta tions of dif fer ent genes (Fig. 3).
It is com monly known that cells elim i nate vi ral nu cle o -
tide se quences with the pe riod of time – it starts with the
elim i na tion of the frag ment of the older se quence and
then spreads to the early re gions of oncoviral ge nome
[23]. As a re sult of some ma lig nantly trans formed cells
there are al most no vi ral nu cle o tide se quences at all.
Sim i lar ef fects have been ob served in the ex per i ments
on trans gen ic an i mals [26–29].
The pos si bil ity of in cor po ra tion of in duced mu ta -
tions to in cor po rate into allogenic nu cle o tide se quences
of cell ge nome has been con firmed by the in vivo ex per -
i ments on both mice and drosophilae [26–29]. The se -
ries of ex per i men tal works by Gazaryan et al. on trans -
gen ic mice with re com bi nant con struc tion pBR322,
con tain ing provirus Rous sar coma, pres ent the in te gra -
tion in sev eral cases of plasmid nu cle o tide se quence
into the mouse ge nome [26–28].
How ever, there is not al ways a link be tween in ser -
tion and mu ta tion. Some times com plete loss of vi ral
nu cle o tide se quences re sulted in the change of the mu -
tant phe no type. Au thors have come to the con clu sion
that transfection can be con sid ered to be the rea son of
MUTAGENESIS IN DUCED BY IN TE GRA TION PRO CESSES
177
Fig.3 Mod el ling of mu ta gen e -
sis and ma lig nant trans for ma -
tion af ter the in tro duc tion of E1
adenovirus (E1A+E1B) trans -
form ing re gion into the cells
in duc tion of cell MGE trans po si tions, re sult ing in lo -
cus-spe cific mu ta tions.
The prog eny of tumorous and trans formed cells,
ob tained us ing oncoviruses, showed the re ar range -
ments as a re sult of con se quent re com bi na tion acts dur -
ing the es tab lish ment of the in te grated con di tion [20].
The place of in cor po ra tion of vi ral and cell genomes
con tains the re ar range ment act, which in cludes de le -
tions, in ser tions, and tan dem du pli ca tions of the in te -
grated frag ment. Chro mo somal DNA, flank ing the in -
te gra tion site, con tains the re gions, ho mol o gous to vi ral
DNA, which may take part in the re com bi na tion acts,
re sult ing in es tab lish ment of the sta ble con di tion.
Some new and big de le tions of cell ge nome oc cur
some times in the course of re com bi na tion (up to 3·103
nu cleo tides).
The study on the mech a nisms of in te gra tion of
DNA-con tain ing vi ruses showed their genomes to be
in cor po rated into both strands of cell DNA – into both
newly syn the sised and the ma trix one [20]. This pro -
cess may ac quire the pat tern of ho mol o gous re com bi -
na tion with sub se quent in ser tion of the exo gen ic nu cle -
o tide se quence. In ad eno vi rus es, the in te gra tion may be
per formed us ing short ho mol o gous re gions be tween vi -
ral and cell se quences sim i larly to the site-spe cific re -
com bi na tion [21–24], how ever, the de tails of this pro -
cess re main un veiled. The in cor po ra tion may take
place us ing the non-ho mol o gous re com bi na tion, pro -
vid ing the in te gra tion of MGE (this is the ba sic mech a -
nism for retro virus es) [8].
Thus, insertional mu ta gen e sis, caused by the in cor -
po ra tion of vi ral genomes into the vi ral DNA is ba si -
cally con nected with the stage of struc tural in sta bil ity
dur ing the es tab lish ment of the in te grated con di tion.
Re gard less of the ab sence of dis tinc tive spec i fic ity of
in cor po ra tion of DNA-con tain ing oncoviruses, the re -
gions of mod er ate re peats are the most pref er a ble for
the reali sa tion of in te gra tion pro cesses. The re gion of
in te gra tion is usu ally lo cated close to the place of tran -
si tion of the unique struc ture of cell ge nome into the re -
peated se quences [20, 22–24]. Pre dom i nant in cor po ra -
tion of oncoviruses into Alu-rich re gions has been
shown. T-an ti gen SV40 and early adenovirus pro teins
were shown to “re cog nise” the point of rep li ca tion of
Alu-se quences as well as it does the cor re spond ing el e -
ment pf vi ral DNA.
The in cor po ra tion into the unique chro mo somal
DNA takes place with the sig nif i cantly lower prob a bil -
ity. There fore, the mu ta gen e sis, in duced by vi ruses in
the unique cell genes may be de ter mined by the
integrational events to a smaller ex tent, than the mu ta -
gen e sis in the heterochromatin re gion.Heterochromatin
is the place of in duc tion of chro mo somal re ar range -
ments [30].
Be sides the in ser tion-de le tion mu ta gen e sis, some
point mu ta tions in the wide range of loci are in duced in
the in te gra tion re gion un der the in flu ence of early reg u -
la tory pro teins [18]. The sys tem of early vi rus genes of
adenovirus is of in ter est due to the fact that it pro vides
the ex am ple of main tain ing the pro cesses of both ma -
lig nant trans for ma tion and mu ta gen e sis. The trans for -
ma tion re gion (operons E1A and E1B) stim u late the
tran scrip tion of nu mer ous cell tar gets, re spon si ble for
the rep li ca tion of DNA and the stim u la tion of cell pro -
lif er a tion, and the early re gion of E4 sup presses the ac -
cu mu la tion of cell mRNA (Fig.5). The same E4 re gion
blocks the ap pear ance of the sec ond, more dis tinct,
peak of in duced mu ta gen e sis at the joint in tro duc tion
into the cells with trans form able E1 re gion or operon
E1B (Fig.3, 6).
Sum ma riz ing on the men tioned-above – it is pos si -
ble to dis tin guish three destabilizing fac tors in the
oncovirus-cell sys tem [12]. The first fac tor of de sta bi li -
sa tion is the ex pres sion of early reg u la tory genes, re -
spon si ble for the stim u la tion of DNA rep li ca tion and
ma lig nant trans for ma tion of cells. The sec ond fac tor is
the re pro gram ming of the cell ge nome (change in ac tiv -
ity and mu ta tion of cell genomes and reg u la tory el e -
ments, MGE trans po si tion) un der the in flu ence of ex -
pres sion of vi ral genes and their in te gra tion into cell
DNA. The ad di tional fac tor, in creas ing the pos si bil ity
of mu ta tions, is the change over of re par a tive and other
DNA-bind ing en zymes to the in ter ac tion with mol e -
cules of ge netic ma trix of exo gen ic or i gin.
Nu mer ous works on the tran si tion of allogenes
show that al most any DNA can in te grate with point cell
ge nome [31–37]. Mam ma lian so matic cells are ca pa ble
of con sum ing the enor mous num bers of mol e cules of
exo gen ic trans form ing DNA. Im por tantly, how ever, in
what mi cro-sur round ing and what reg u la tory el e ments
are used to in tro duce the transgene into the cells. If
exo gen ic DNA mol e cules are in ac ti vated and/or do not
LUKASH L. L.
178
con tain ge netic el e ments or genes, in flu enc ing the in te -
gra tion, then this pro cess is per formed by means of cell
en zy matic sys tem only. The tech nique of trans po si tion
of cells into mam ma lian so matic cells is im por tant too.
The mu ta tion fre quency in the case of DNA in tro duc -
tion us ing the method of microinjections is higher, than
that of the retro virus in fec tion, which is, ev i dently, con -
nected with the specificities of in te gra tion mech a nisms.
The pos si bil ity of in duced mu ta tions at the in te gra -
tion of allogenic nu cle o tide se quences into the cell ge -
nome was dem on strated in the case of mam ma lian so -
matic cells in the cul ture [31–37] and in the in vivo ex -
per i ments on mice and drosophilae [26–29]. As it has
been no ticed above, trans gen ic mice, con tain ing re com -
bi nant con struc tion with in cor po rated Rous sar coma
provirus, wash shown to be in cor po rated into plasmid
nu cle o tide se quence in mouse ge nome [26]. How ever,
the di rect con nec tion be tween in ser tions with mu ta -
tions has not al ways been re vealed, there fore, au thors
make the con clu sion that transfection re sults in in duc -
tion of trans po si tions of cell MGE, in duc ing lo cus-spe -
cific mu ta tions.
The pro cess of in te gra tion of trans form ing DNA
into cell heterochromatin can be di vided into the same
stages of evo lu tion of exo gen ic nu cle o tide se quences as
at the in cor po ra tion of DNA-con tain ing oncoviruses:
1.) tem po rary ex pres sion of trans form ing genes and the
for ma tion highly-mo lec u lar com plexes, pecelasomes;
2.) es tab lish ment of in te grated con di tion and struc tural
in sta bil ity; 3.) sta ble ge netic trans for ma tion; 4.) func -
tional in ac ti va tion and struc tural dis in te gra tion of
allogenic nu cle o tide se quences of ge nome cells.
The con di tion of in te gra tion sta bi lises af ter the
whole se ries of re ar range ments and se lec tions in a long
time af ter transfection. The level of in ser tions in
syngeneic an i mals is app. 8%, which is very close to the
re sults, ob tained for retro-vi ruses in mam ma lian so -
matic cells [26–29].
More and more data on insertional mu ta gen e sis
dur ing the transgene in te gra tion, caus ing the dis or ders
MUTAGENESIS IN DUCED BY IN TE GRA TION PRO CESSES
179
Fig.4 Se quence of integrational and mutational events in adenovirus-cell sys tem
in genes, in volved in embryogenesis and cell dif fer en ti -
a tion, is be ing pre sented [33]. Some cases were spe -
cific for de ter min ing the gene, the dis or ders of which
dur ing the provirus in te gra tion, re sulted in mu ta tion.
Thus, the retro virus in cor po ra tion into the col la gen
gene re sulted in em bry onic death on the 6th and the 12th
day [34]. An other insertional mu ta tion is caused, ap -
par ently, by the pen e tra tion of transgene into the re gion
of ge nome, re spon si ble for morphogenesis of ex trem i -
ties in mice [35].
The dif fer ence of exo gen ic DNA as “liv ing”
mutagen from phys i cal and chem i cal muta gens is in the
ca pa bil ity to be “grafted-in”, which in creases sig nif i -
cantly the time of its pres ence in the cell. The pro cess
of sort of in ves ti ga tion-and-cull ing of allogenic ma te -
rial is con cluded with the for ma tion of new highly-mo -
lec u lar ge netic struc tures – pecelasomes – which are ca -
pa ble of in volv ing into the acts of re com bi na tion with
chro mo somal DNA [31–37]. Dur ing the cap tur ing of
centromere by pecelasome, there may be formed a new
mini-chro mo some on its base. Some times, newly
formed mini-chro mo somes are in te grated into the host
chro mo somes and be come a part of cell ge nome. In
some cases allogenic DNA re mains the in de pend ently
rep li cated struc ture.
The pres ence of chro mo somal re gions (the re gions
of con cen tra tion of Alu-re peats), sen si tive to the in flu -
ence of trans form ing DNA, was de ter mined sim i larly
as well as in the ex per i ments on vi ruses. The anal y sis
of the data bulk re vealed that it is Alu-el e ments that may
be the “hot spots” of re com bi nant and mutational
events, as well as to be the me di a tors of ho mol o gous
and non-ho mol o gous recombinations [38, 39].
Evolutional de vel op ment of chro mo somal ap pa -
ra tus. Com par a tive cy to log i cal anal y ses re vealed the
sig nif i cant role in the spe cies-for ma tion in plants is
played by polyploidisation. How ever, polyploidy in
an i mals re sulted in dis or ders of chro mo somal mech a -
nism of gen der de ter mi na tion, that is why this pro cess
was not so im por tant in their evo lu tion; al most all not
LUKASH L. L.
180
Fig.5 In te gra tion of early operons of adenovirus and their in flu ence on the ex pres sion of cell genes
nu mer ous polyploidy spe cies are mul ti plied par the no -
ge net i cally. The evo lu tion ary sig nif i cance of var i ous
chro mo somal re ar range ments – du pli ca tions, in ver -
sions, translocations – has been dem on strated [5]. At
the same time, the spe cial role of du pli ca tions as the ba -
sic means of in crease in pop u la tion and di ver sity of
genes in the course of evo lu tion ary de vel op ment of or -
gan isms.
The set of chro mo somes – karyotype – is the re li -
able char ac ter is tic of be long ing to a cer tain spe cies of
an i mals or plants. It is true for the ma jor ity of spe cies,
yet for not all of them. Many an i mals and plants are
spe cific for spe cific for ad di tional sets of chro mo somes
(so called, B-chro mo somes) along with the ba sic sets
(A-chro mo somes) (Fig.7). The sizes and the forms of
the for mer may dif fer, de pend ing on the rep re sen ta tives
of the same spe cies. For ex am ples, the karyotype of
Asian wood mouse (Apodemus sylvaticus) con sists of
23 pairs of autosomes, sex chro mo somes, and nine
B-chro mo somes [40].
The ap pli ca tion meth ods of mo lec u lar ge net ics al -
lowed to de ter mine that B-chro mo somes con sists 100%
of sur plus DNA, while all B-chro mo somes pos sess
com mon DNA re peats. Later on, their af fin ity in some
DNA-re peats with A-chro mo somes has been re vealed.
It has been re vealed that near-centromeric re gions
of B-chro mo somes con tain the re peats, af fined with the
se quences, lo cated in the near-centromeric re gions of
autosomes and in the dense blocks of sex chro mo -
somes. More de tailed anal y sis of these re gions by
DNA-probes re vealed some thing more be yond the af -
fin ity of A- and B-chro mo somes. When the A-chro mo -
somes prep a ra tions were ap plied with B-chro mo somes
la belled probes, it has been noted that the la bel has been
ob served not only in centromeric re gions but also in the
arm of autosome, yet the stain ing in dex was many times
lower.
The use of la belled probes al lowed dis cov er ing one
more in ter est ing spec i fic ity of B-chro mo somes,
namely, B-chro mo somes are isochromosomes. Such
chro mo somes with ab so lutely iden ti cal arms oc cur due
to the re ar range ments in can cer cells, as well as in vi tro
cul ti vated cells, yet they hardly ever oc cur in the norm.
Re gard ing B-chro mo somes of wood mouse – all most
all of them are isochromosomes. Stain ing of wood
mouse chro mo somes us ing B-chro mo somal probes
showed that the ge nome of this spe cies con tains at least
three types of re peats as fol lows: 1.) local ised in
near-centromeric re gions of B-chro mo somes and
autosomes, as well as in two re gions of sex chro mo -
MUTAGENESIS IN DUCED BY IN TE GRA TION PRO CESSES
181
Fig.6 Reg u la tion of
mu ta gen e sis by the
sys tem of early
operons of
adenovirus
somes; 2.) com pris ing the bulk of the arms of B-chro -
mo somes and pres ent in A-chro mo somes in smaller
amounts; 3.) de tected at the ends of some B-chro mo -
somes.
The anal y sis of sets of chro mo somes of close spe -
cies al lowed to put for ward the sup po si tion of
hypothetic pic ture of ap pear ance and evo lu tion of
B-chro mo somes (Fig.8). Ini tially, some MGE en tered
near-centromeric se quences of autosomes and then,
hav ing cap tured centromeric and telomeric se quences
of host DNA, be came chro mo somes. The pres ence of
centromere al lows par tic i pat ing in the pro cess of cell
di vi sion along the main chro mo somes, while telomeres
pro tect the ends of newly-formed chro mo somes from
de struc tion. As soon as B-chro mo somes oc curred, they
have at tracted some other MGE, pres ent in the cell.
Ter mi nal re peats were in te grated the last into B-chro -
mo somes; the im pos si bil ity of their dense pack ing in
the mo ment of di vi sion tes ti fies in fa vour of their ex -
tra-chro mo somal or i gin. It has been showed also that
some B-chro mo somes con tain some genes, re spon si ble
of syn the sis with ri bo somal RNA. It is also pos si ble
that, hav ing cap tured some other use ful genes, they will
turn into A-chro mo somes with the pe riod of time? As
not all of the wood mouse spe cies have got the B-chro -
mo somes, it is sup posed that they in her ited them from a
com mon an ces tor not the B-chro mo somes proper, but
the ca pa bil ity to form them de novo.
The scheme pre sented de scribes the ap pear ance of
new chro mo somes and, con se quently, the ex pand ing of
ge nome. Yet the ques tion still re mains, how can ge -
nome de crease rap idly in size?
Pos si ble an swer for this ques tion is pro vided by the
data of chromatin dim i nu tion. The no tion of chromatin
dim i nu tion in Ascaridae was dis cov ered by T. Boveri
in 1887 [3]. It has been shown that dif fer en ti a tion of
cell on of germ track and the soma are ac com pa nied by
the par tial loss of ge netic ma te rial at early em bry onic
de vel op ment (chromatin dim i nu tion, elim i na tion of
chro mo somes) is rather com mon in the na ture [3, 13,
41–43]. Chromatin dim i nu tion is, to some ex tent, pres -
ent in some spe cies of as ca rids, cy clops, infusoria, chig -
gers, sliv ers, lepidopterans, flies, and fishes. The loss
of nu cleus by the eryth ro cytes dur ing the dif fer en ti a tion
in hu man may be con sid ered as the ex traor di nary case
of dim i nu tion.
Chromatin dim i nu tion cor re sponds to the con cept
of macromutations on the level of chro mo somal phe no -
LUKASH L. L.
182
Fig.7 Or gani sa tion of
ba sic and ad di tional
chro mo somes of
mam mals [41]
type [3]. Chromatin dim i nu tion in the listed-above or -
gan isms is, on the one hand, the clas si cal form of to tal
re duc tion of the ge nome dur ing ontogenesis at dif fer en -
ti a tion of cells, while, on the other hand, it is the pos si -
ble model for sim i lar ge nome trans for ma tions of
eukaryotes in the course of evo lu tion. The lat ter is the
proper rea son for dwell ing upon this is sue in cur rent re -
view.
As it has been shown in dip ter ans, elim i na tion of
cer tain chro mo somes is one of the phe nom ena of dim i -
nu tion; yet, it is quite pos si ble, that no sig nif i cant mo -
lec u lar re ar range ments of the struc ture of chro mo somal
DNA takes place [43].
Chromatin dim i nu tion out of em bry onic so matic
cells in Cy clops kolensis is spe cific for the re cord DNA
quan tity for multi-cel lu lar or gan ism (94%) [13]. It is
not much lees than in the case of hypotricha – the ab so -
lute re cord. How ever, the loss of the big ger part of
DNA has no ef fect on the num ber of chro mo somes – it
re mains con stant – 22 (the same num ber as in the cells
of germ track). What con clu sions can be made re gard -
ing the role of sur plus DNA for the in ves ti ga tion of
chromatin dim i nu tion in cy clops?
First of all, only 6% of chro mo somal DNA is
enough dif fer en ti a tion, histogenesis and body for ma -
tion of in the case of C. kolensis. This im plies 94% of
DNA con tains nei ther genes nor reg u la tory se quences,
nec es sary for in di vid ual de vel op ment of a given spe -
cies.
Sec ondly, chromatin dim i nu tion is quan ti ta tively
strictly re peated in the course of ev ery re pro duc tion cy -
cle of cyclop (10 years of ob ser va tions), which is pos si -
ble only if germ track cell DNA is not af fected by dim i -
nu tion and is pre served as long as the spe cies ex ists.
There fore, the DNA, re moved from chro mo somes
dur ing the dim i nu tion can not be con sid ered to be the
“junk” one. More over, it is con sid ered as sur plus for
so matic cells only, and not for the cells of germ track.
The pro cess of dim i nu tion is a vivid ex am ple of nat u ral
gene en gi neer ing. The main con se quence of the dim i -
nu tion phe nom e non is in the fact that the genes, tak ing
part in the in di vid ual de vel op ment, can be nei ther lost
nor dam aged, i.e. sta bil ity of ge netic ma te rial has to be
main tained at a very high level.
The dim i nu tion en zymes cut and link back the chro -
mo somal DNA. They per form these func tions fault -
lessly, as the dis rup tion sites are strictly de fined (Fig.9).
Such gene en gi neer ing op er a tions are far away from
those avail able to the sci en tists ma nip u la tion-ac cu -
racy-wise, per formed by cell en zymes. Once mu ta tions
oc cur, em bry onic de vel op ment of this gene is go ing to
stop only when the pe riod of func tion ing has come.
An other vari ant of fault cut ting is the chro mo somal
re ar range ments, which are also le thal. How ever, the
num ber of spon ta ne ous chro mo somal re ar range ments
in the course of early de vel op ment of cy clops is strik -
ingly small – app. 100 times smaller than in hu man
lym pho cytes, clas si cal ob ject for test ing of chro mo -
MUTAGENESIS IN DUCED BY IN TE GRA TION PRO CESSES
183
Fig.8 Or i gin and evo lu tion of ad di -
tional B-chro mo somes of Asian
wood mouse (Apodemus
sylvaticus)
somal mu ta tions. This fact tes ti fies in fa vour of the
pres ence of a pow er ful reg u la tory sys tem against mu ta -
tions, act ing, at least, in the time when the level of en zy -
matic ac tiv ity in the cell is very high. The lat ter has to
“at tack” the spec i fied DNA re gions only. Is any new
re gions, sen si tive to these en zymes, oc curred as a re sult
of mu ta tions, they would have been cut out and de leted
of the ge nome. But if only one cell, which would be
par ent for the de vel op ment of not so matic line but the
germ line, was sub jected to dim i nu tion, then it would
thread not the an i mal unit only, but for the spe cies in
gen eral, as it would in ev i ta bly re sulted in in fer til ity of
the or gan ism with non-pro grammed loss of ge netic ma -
te rial.
The re gions of cut-out DNA are gath ered in gran -
ules sur rounded by firm mem brane. Mo lec u lar and ge -
netic anal y sis re vealed DNA to con tain re peated nu cle -
o tide se quences of high homology. The for ma tion of
these se quences is re lated to the con cert evo lu tion and
two rea sons for their for ma tion are con sid ered: the first
one – re cent der i va tion of re peats from the main an ces -
tral; the sec ond – recombinational events. If the ho mol -
o gous re gions are lo cated in the nu cleus in such a way
that re com bi na tion may take place, newly oc curred mu -
ta tions will be elim i nated as a re sult of recombinational
acts and homo logues will be re tained [41, 42].
What is the des ig na tion of sur plus DNA, elim i nated
af ter dim i nu tion? Ac cord ing to Akifjev et al., the only
con sis tent ex pla na tion of the role of sur plus DNA in the
germ track cells is that sur plus DNA cre ates a unique
pic ture of the spe cies and is con sid ered to be the fac tor
of its ge netic iso la tion [13, 41]. If this pic ture had not
been kept through out the gen er a tions, syn op sis of ho -
mol o gous chro mo somes in mei o sis would have been
dis torted and the prog eny would be come aneuploidy
(i.e. aliquant num ber of chro mo somes to the hap loid
one) with no pos si ble chances to sur vive.
Heterochromatin is one of the most stud ied DNA
com po nents. The func tions of heterochromatin in the
cells are di verse and are the is sue of spe cial im por tance
[3]. The cases of heterochromatin dim i nu tion re viewed
in wide range of or gan isms re veal con clu sively that the
func tions of the ma jor part of heterochromatin may be
lim ited by the germ track cells. The higher is the dif fer -
ence in mo lec u lar struc ture of non-en cod ing re gions,
the higher is the pos si bil ity of dis or ders in con ju ga tion
of homo logues with all con se quences fol lowed. This is
the key fac tor to stop hy bridi sa tion of close spe cies
(along with other iso lat ing mech a nisms).
The in ves ti ga tion per formed show that chromatin
dim i nu tion re quires co or di nated work of the clus ters of
doz ens of genes, i.e. this pro cess is un der tough ge netic
LUKASH L. L.
184
Fig.9 Scheme of dim i nu tion of chromatin in cy clops [13]
con trol. Es sen tially, chromatin dim i nu tion at the level
of chro mo somal ap pa ra tus matches the no tion of reg u -
lated macromutations [3]. It is pos si ble that the change
of gene mu ta tion programme is ac com pa nied by the ini -
ti a tion of reg u la tory pro cesses of mutational and re -
com bi nant vari abil ity [10].
Re gard less of the fact that chromatin dim i nu tion
has oc curred and se cured in only some or gan isms, it
may be a good ex am ple for mod el ling of sim i lar trans -
for ma tions in eukaryotic ge nome in the course of evo -
lu tion. This ex am ple al lows ap proach ing the prob lem
of de creas ing genomes in the evo lu tion of close spe cies.
Thus, if in the pro cess of chromatin dim i nu tion, the
cells sub jected to re moval are those of DNA, par ent to
germ track and the pro cess is not ac com pa nied by the
le thal event, as this pro cess in volves non-en cod ing
DNA only, than all ga metes of this or gan ism will ac -
quire new re duces ge nome. The whole se ries of in di -
vid ual or gan isms will ac quire it, which will re sult in
cre ation of the iso lated group. Sup pos edly, this was the
way that evo lu tion of or gan isms, which se cured
chromatin dim i nu tion, has gone through. The no tion of
dim i nu tion is ap pli ca ble for sys tem ati sa tion of Cy -
clops, as the dif fer ences in mor phol ogy be tween close
spe cies are very small.
Other spe cies ob tained dif fer ent ways to in ac ti vate,
i.e. to “calm down” the sur plus DNA. Around 50% of
hu man ge nome genes are known not to take part in gene
ex pres sion at all. The whole re gions are of ten un reach -
able for tran scrip tion due to highly-com pact ar range -
ment of chro mo somal re gions. The way of chang ing
the ge netic ma te rial in this case is dif fer ent, but the re -
sult re mains the same – iso la tion of some ge nome re -
gions [13].
Thus, the fol low ing con clu sions can be made:
The sys tems of MGE of eukaryotic genomes are the
sources and the mech a nisms of insertional vari abil ity,
they in flu ence the ex pres sion of qual i ta tive and quan ti -
ta tive fea tures, change the pat terns of MGE lo cal isa tion
in ac cor dance to fea tures and stress ef fect as a re sponse
to the ex ter nal se lec tion. MGE per form the role of
some sort of re cep tors of stress sig nals, which ini ti ate
the out breaks of transpositional vari abil ity in the crit i -
cal pe ri ods of evo lu tion, re sult ing in the trans for ma tion
of homeostatic spe cies norm.
The cells are ca pa ble of form ing new
macromolecular com plexes, con sist ing of DNA-re -
peats, which are in cor po rated pre dom i nantly in the
instable heterochromatin re gions (Alu-re peats in hu man
ge nome).
Au ton o mous macromolecular com plexes
(pecelasomes) may cap ture centromeres and trans form
into mini-chro mo somes, which will be later de vel oped
into in de pend ent ge netic struc tures.
Macro-mu ta tions at the in ter ac tion of main cell and
ad di tional chro mo somes (as in the case of A- and
B-chro mo somes of wood mouse) may the source of far -
ther ge nome evo lu tion. De le tions of the re peated nu -
cle o tide se quences out of heterochromatin re gions may
re sult in fast ge nome de crease (as it hap pened in the
cases of evo lu tion of some spe cies, which se cured the
mech a nism of chromatin dim i nu tion).
Sig nif i cant re or gani sa tions of ge nome in the course
of in te gra tion pro cesses are likely to be ac com pa nied
by the in crease in the rate of point mu ta tions in the wide
range of loci un der the in flu ence of en zy matic sys tems
of ac ti va tion, which pro vide the ba sic ma trix pro cesses,
i.e. rep li ca tion, re com bi na tion, rep a ra tion, mod i fi ca -
tion, and re stric tion.
Ë. Ë. Ëóêàø
Ìóòàãåíåç ïðè èíòåãðàöèîííûõ ïðîöåññàõ è ýâîëþöèÿ
ÿäåðíîãî ãåíîìà
Ðåçþìå
Ðàññìîòðåíû âîïðîñû ìóòàöèîííîé èçìåí÷èâîñòè,
âûçûâàåìîé êðóïíûìè ñòðóêòóðíûìè ïåðåñòðîéêàìè
ãåíåòè÷åñêîãî ìàòåðèàëà, òàêèìè êàê òðàíñïîçèöèè
ìîáèëüíûõ ãåíåòè÷åñêèõ ýëåìåíòîâ, èíòåãðàöèÿ èëè
äåçèíòåãðàöèÿ ýêçîãåííûõ íóêëåîòèäíûõ
ïîñëåäîâàòåëüíîñòåé âèðóñíîé è íåâèðóñíîé ïðèðîäû,
èçìåíåíèÿ õðîìîñîìíîãî íàáîðà èëè îòäåëüíûõ õðîìîñîì,
äèìèíóöèÿ õðîìàòèíà, è ðîëü òàêîé èçìåí÷èâîñòè â ýâîëþöèè
ÿäåðíîãî ãåíîìà.
Êëþ÷åâûå ñëîâà: ìóòàãåíåç, ýâîëþöèÿ, ÿäåðíûé ãåíîì,
ãåòåðîõðîìàòèí, ìîáèëüíûå ãåíåòè÷åñêèå ýëåìåíòû,
õðîìîñîìà, äèìèíóöèÿ õðîìàòèíà.
MUTAGENESIS IN DUCED BY IN TE GRA TION PRO CESSES
185
REFERENCES
1. Êîðäþì Â. À. Îïóõîëü – êàê îíà âèäèòñÿ ñåãîäíÿ ñ
ïîçèöèé ìîëåêóëÿðíîé ãåíåòèêè // Áèîïîëèìåðû è
êëåòêà.–2001.–17, ¹ 2.–Ñ. 109–139.
2. Ãëàçêî Â. È. Ãåíåòè÷åñêè ìîäèôèöèðîâàííûå
îðãàíèçìû: îò áàêòåðèé äî ÷åëîâåêà.–Êèåâ: Ìèí-âî
îáðàçîâàíèÿ è íàóêè Óêðàèíû, 2002.–210 ñ.
3. Æèìóëåâ È. Ô. Îáùàÿ è ìîëåêóëÿðíàÿ
ãåíåòèêà.–Íîâîñèáèðñê: Ñèá. óíèâåðñèòåòñêîå èçä-âî,
2003.–480 ñ.
4. Èíãå-Âå÷òîìîâ Ñ. Ã. Ãåíåòèêà ñ îñíîâàìè
ñåëåêöèè.–Ì.: Âûñø. øê., 1989.–Ñ. 290–369.
5. Ãåðøåíçîí Ñ. Ì. Îñíîâû ñîâðåìåííîé ãåíåòèêè.–Êèåâ:
Íàóê. äóìêà, 1983.–240 ñ.
6. Ãåðøåíçîí Ñ. Ì. Ìóòàöèè.–Êèåâ: Íàóê. äóìêà, 1991.–
111 ñ.
7. Æåñòÿíèêîâ Â. Ä. Ðåïàðàöèÿ ÄÍÊ è åå áèîëîãè÷åñêîå
çíà÷åíèå.–Ëåíèíãðàä: Íàóêà, 1979.–286 ñ.
8. Õåñèí Ð. Á. Íåïîñòîÿíñòâî ãåíîìà.– Ì.: Íàóêà, 1984.–
472 ñ.
9. Àëåêïåðîâ Ó. Ê. Àíòèìóòàãåíåç.–Ì.: Íàóêà, 1984.–100 ñ.
10. Cer van tes R. B., Stringer J. R., Shao C., Tischfield G. A.,
Stambrook P. G. Em bry onic stem cells and so matic cells dif -
fer in mu ta tion fre quency and type // Proc. Nat. Acad. Sci.
USA.–2002.–99.–P. 3586–3590.
11. Øàïèðî Í. È., Âàðøàâåð Í. Á. Î òåìïå ñïîíòàííîãî
ìóòàöèîííîãî ïðîöåññà â ñîìàòè÷åñêèõ êëåòêàõ
ìëåêîïèòàþùèõ è î íåêîòîðûõ âîïðîñàõ, ñ íèì
ñâÿçàííûõ // Ãåíåòèêà.–1976.–12, ¹ 7.–Ñ.132–149.
12. Ëóêàø Ë. Ë. Ðåãóëÿöèÿ èçìåí÷èâîñòè ãåíîìà
ñîìàòè÷åñêèõ êëåòîê ìëåêîïèòàþùèõ ïîä âëèÿíèåì
ýêçîãåííûõ áèîëîãè÷åñêèõ ôàêòîðîâ // Á³îïîë³ìåðè ³
êë³òèíà.–2004.–20, ¹ 1–2.–Ñ. 93–105.
13. Àêèôüåâ À. Ï. Èçáûòî÷íàÿ ÄÍÊ – ãåíåòè÷åñêàÿ
êâàäðàòóðà êðóãà? //
http:/vivovoco.rsl.ru/VV/JOURNAL/NA-
TURE/10_04/EXCESS.HTM – À. Ï. Àêèôüåâ //
Ïðèðîäà.–2004.–¹ 10.
14. Àêèôüåâ À .Ï. Ìîë÷àùàÿ ÄÍÊ è åå ðîëü â ýâîëþöèè //
Ïðèðîäà.–1974.–¹ 9.–Ñ. 49–54.
15. Ãâîçäåâ Â. À. Ïîäâèæíàÿ ÄÍÊ ýóêàðèîò. 2. Ðîëü â
ðåãóëÿöèè àêòèâíîñòè ãåíîâ è ýâîëþöèè ãåíîìà //
Ñîðîñîâñêèé îáðàçîâàò. æóðí.–1998.–¹ 8.–Ñ. 15–21.
16. Ðàòíåð Â. À., Âàñèëüåâà Ë. À. Èíäóêöèÿ òðàíñïîçèöèé
ìîáèëüíûõ ãåíåòè÷åñêèõ ýëåìåíòîâ ñòðåññîâûìè
âîçäåéñòâèÿìè // Ñîðîñîâñêèé îáðàçîâàò. æóðí.–2000.–
¹ 6.–Ñ. 14–20.
17. Ðàòíåð Â. À., Âàñèëüåâà Ë. À. Ìîáèëüíûå ãåíåòè÷åñêèå
ýëåìåíòû (ÌÃÝ) è ýâîëþöèÿ ãåíîìîâ // http://macroevo-
lution.narod.ru/ratner1.htm – ìîáèëüíûå ãåíåòè÷åñêèå
ýëåìåíòû.
18. Ëóêàø Ë. Ë. Äåñòàáèëèçàöèÿ êëåòî÷íîãî ãåíîìà ïîä
âëèÿíèåì ýêñïðåññèè ðàííèõ ðåãóëÿòîðíûõ ãåíîâ
îíêîâèðóñîâ // Öèòîëîãèÿ è ãåíåòèêà.–2002.–36, ¹ 2.–Ñ.
68–80.
19. Ëóêàø Ë. Ë. Áèîëîãè÷åñêèå ìóòàãåíû: èõ âëèÿíèå íà
ñòàáèëüíîñòü ýóêàðèîòè÷åñêèõ êëåòî÷íûõ ñèñòåì //
³ñí. óêðà¿íñüêîãî òîâ-âà ãåíåòèê³â òà
ñåëåêö³îíåð³â.–2003.– ¹ 1.–Ñ. 62–81.
20. Àãååíêî À. È. Îíêîãåíû è êàíöåðîãåíåç.–Ì.: Ìåäèöèíà,
1986.–T. 256.–152 ñ.
21. Ïîïîâ Ë. Ñ., Ãîðáóíîâà Ë. Â., Âàðøàâåð Í. Á.
Èíòåãðàöèÿ ÄÍÊ ÎÂ40 â ãåíîì êëåòîê è âèðóñíûé
ìóòàãåíåç // Ãåíåòèêà.–1986.–22, ¹ 9.–Ñ. 2213–2219.
22. Doerfler W. Up take, fix a tion and ex pres sion of for eign
DNA in mam ma lian cells: the or ga ni za tion of in te grated
adenovirus DNA se quences // Curr. Top. Microbiol. Immu-
nol.–1982.–101.–P. 128–188.
23.Kuhlmann J., Doerfler W. Loss of vi ral genomes from ham -
ster tu mor cells and nonrandom al ter ations in pat terns of
methylation of in te grated adenovirus type 12 DNA // J.
Virol.–1983.–147.–P. 631–636.
24. Schultz H. M., Doerfler W. De tec tion of cel lu lar DNA at site
of vi ral DNA in ser tion in the adenovirus type 12-in duced
mouse tu mor CBA-12-1-T // Nucl. Ac ids Res.–1984.–12.–
P. 4959–4976.
25. Ëóêàø Ë. Ë., Ëóêàø Ñ. È., Çàäîðîæíûé Â. Ô.
Ìàòåìàòè÷åñêàÿ ìîäåëü äèíàìèêè ìóòàãåíåçà,
èíäóöèðîâàííîãî ôðàãìåíòîì ÄÍÊ àäåíîâèðóñà, â
êëåòêàõ ìëåêîïèòàþùèõ // Áèîïîëèìåðû è
êëåòêà.–1996.–12, ¹ 3.–Ñ. 7–16.
26. Ãàçàðÿí Ê. Ã. Ìèêðîèíúåêöèè ãåíîâ â çèãîòû è
ýìáðèîíû: èíòåãðàöèÿ â ãåíîì è ãåíåòè÷åñêèå ýôôåêòû
// Óñïåõè ñîâðåì. ãåíåòèêè.–1985.–¹ 13.–Ñ. 75–88.
27. Òàðàíòóë Â. Ç., Êóçíåöîâà Å. Ä., Ãàçàðÿí Ê. Ã.
Õàðàêòåðèñòèêà ó÷àñòêîâ ãåíîìà òðàíñãåííûõ
æèâîòíûõ, ïðèëåãàþùèõ ê èíòåãðèðîâàííûì
ïîñëåäîâàòåëüíîñòÿì ÷óæåðîäíîé ÄÍÊ // Ìîëåêóëÿð.
áèîëîãèÿ.–1989.–23, ¹ 4.– Ñ. 1036–1040.
28. Íàáèðî÷êèí Ñ. Ä., Ãàáèòîâà À. Á., Áåãåòîâà Ò. Ñ.,
Ãàçàðÿí Ê. Ã. Èíäóêöèÿ íåñòàáèëüíûõ ìóòàöèé ó
Drosophila melanogaster ìèêðîèíúåêöèåé ÄÍÊ
îíêîãåííûõ âèðóñîâ â ïîëÿðíóþ ïëàçìó ýìáðèîíîâ.
Ìàëèãíèçèðóþùèé ýôôåêò îíêîâèðóñíûõ ÄÍÊ //
Ìîëåêóëÿð. áèîëîãèÿ.–1991.–24, ¹ 5.–Ñ. 783–789.
29. Gordon J. W. A for eign dihydrofolate reductase gene in
trans gen ic mice acts as dom i nant mu ta tion // Mol. Cell.
Biol.–1986.–6.–P. 2158–2167.
30. Akifyev A. P. Mech a nisms of the pro duc tion of chro mo -
somal ab er ra tions in eukaryotic cells // Physiol., Gen eral.
Biol. Rev.–1995.–10.–P. 1–56.
31. Òîìèëèí Í. Â. Ãåíåòè÷åñêàÿ ñòàáèëüíîñòü
êëåòêè.–Ëåíèíãðàä: Íàóêà, 1983.–196 ñ.
32. Palmiter R. D., Brinster R. L., Ham mer R. E. Dra matic
growth of mice de velop from eggs microinjected with
methallothionein-growth hor mone fu sion genes // Na -
ture.–1982.–300.–P. 611–615.
33. Wilkie T. M., Palmiter R. D. Anal y sis of the integrant in
Myk-103 trans gen ic mice in which males fail to trans mit the
integrant // Mol. Cell. Biol.–1987.–7.–P. 1646–1655.
34. Harbers K., Kuehn M., Delins H., Jaenish R. In ser tion of
gene leads to em bry onic le thal mu ta tion in mice // Proc. Nat.
Acad. Sci. USA.–1984.–81.–P. 1504–1508.
35. Hanahan D. Her i ta ble for ma tion of pan cre atic B-cell tu -
mors in trans gen ic mice ex press ing re com bi nant in su -
lin/sim ian vi rus 40 onco genes // Na ture.–1985.–315.–P.
115–122.
36. Áîáðûøåâà È. Â., Áàðîí Å. Ì., Âàðøàâåð Í. Á. Ïëàçìèäà
pSVc-myc-1 èíäóöèðóåò ãåííûå ìóòàöèè è õðîìîñîìíûå
àáåððàöèè â êóëüòèâèðóåìûõ êëåòêàõ êèòàéñêîãî
õîìÿ÷êà // Öèòîëîãèÿ è ãåíåòèêà.–1993.–27, ¹ 4.–Ñ.
51–56.
37. Áîáðûøåâà È. Â., Âàðøàâåð Í. Á. Õàðàêòåðèñòèêà
ìóòàíòîâ, èíäóöèðîâàííûõ îíêîãåíîì c-Ha-ras1, è
ïðèðîäà ìóòàãåííîãî äåéñòâèÿ îíêîãåíà //
Ãåíåòèêà.–1995.–31, ¹ 12.–Ñ. 1598–1604.
38. Øàõìóðàäîâ È. À., Êàïèòîíîâ Â. Â., Êîë÷àíîâ Í. À.,
Îìåëüÿí÷óê Ë. Â. Ýâîëþöèÿ ïîâòîðîâ Alu: äèíàìèêà
ðàñïðîñòðàíåíèÿ â ãåíîìå // Ãåíåòèêà.–1989.– 25, ¹ 9.–
Ñ. 1682–1689.
39. Ëóêàø Ë. Ë., Øâà÷êî Ë. Ï., Êîñòåöêàÿ Å. Â. Ìîáèëüíûå
ãåíåòè÷åñêèå ýëåìåíòû â ïðîöåññàõ ìóòàãåíåçà,
ðåêîìáèíàöèè è çëîêà÷åñòâåííîé òðàíñôîðìàöèè
LUKASH L. L.
186
êëåòîê ÷åëîâåêà // Áèîïîëèìåðû è êëåòêà.–1996.–12, ¹
2.– Ñ. 7–19.
40. Ðóáöîâ Í. Á., Áîðîäèí Ï. Ì. Ýâîëþöèÿ õðîìîñîì: îò À
äî Â è îáðàòíî //
http:/vivovoco.rsl.ru/VV/JOURNAL/NATU-
RE/03_02/NATI.HTM. – Í. Á. Ðóáöîâ // Ïðèðîäà.–
2002.–¹ 3.
41. Àêèôüåâ À. Ï., Õóäîëèé Ã. À. Ìóòàãåíåç è ãåíåòè÷åñêèé
ãîìåîñòàç ó âûñøèõ îðãàíèçìîâ // Âåñòí. ÐÀÌÍ.–1993.–
¹ 1.– Ñ. 3–9.
42. Àêèôüåâ À. Ï., Ãðèøàíèí À. Ê., Äåãòÿðåâ Ñ. Â.
Äèìèíóöèÿ õðîìàòèíà – êëþ÷åâîé ïðîöåññ äëÿ
îáúÿñíåíèÿ ïàðàäîêñà ðàçìåðà ãåíîìà ýóêàðèîò è
íåêîòîðûõ ìåõàíèçìîâ ãåíåòè÷åñêîé èçîëÿöèè //
Ãåíåòèêà.–2002.–38.– Ñ. 595–606.
43. Ãðèøàíèí À. Ê., Øåõîâöîâ À. Ê., Áîéêîâà Ò. Â., Àêèôüåâ
À. Ï., Æèìóëåâ È. Ô. Ïðîáëåìà äèìèíóöèè õðîìàòèíà íà
ðóáåæå ÕÕ è ÕÕ1 âåêîâ // Öèòîëîãèÿ.–2006.–48, ¹ 5.–
Ñ.379–397.
ÓÄÊ 577.21+575.857
Íàä³éøëà äî ðåäàêö³¿ 24.05.07
187
MUTAGENESIS IN DUCED BY IN TE GRA TION PRO CESSES
|