WO2024253600A1 - Procédé d'estimation des proportions de mélanges d'adn acellulaire à partir de fragments issus des télomères - Google Patents

Procédé d'estimation des proportions de mélanges d'adn acellulaire à partir de fragments issus des télomères Download PDF

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WO2024253600A1
WO2024253600A1 PCT/SK2023/000005 SK2023000005W WO2024253600A1 WO 2024253600 A1 WO2024253600 A1 WO 2024253600A1 SK 2023000005 W SK2023000005 W SK 2023000005W WO 2024253600 A1 WO2024253600 A1 WO 2024253600A1
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dna
telomere
fetal
cell
maternal
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Juraj GAZDARICA
Daria ČÁRSKA
Jaroslav BUDIŠ
Jakub STYK
Ondrej PÖS
Zuzana HOLEŠOVÁ
Ján RADVÁNSZKY
Tomáš SZEMES
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Geneton S R O
Univerzita Komenskeho
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Geneton S R O
Univerzita Komenskeho
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6869—Methods for sequencing

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  • the invention relates to the field of liquid biopsy testing.
  • the invention provides a method for estimation of the proportion of various components of analyzed DNA mixture with various clinical applications, such as non-invasive prenatal testing and oncology screening.
  • Genome is physically stored in a double helix DNA molecule, which consists of two strands, each carrying a sequence of nucleotides (A, T, G, C) called bases.
  • a whole human genome is a sequence of roughly 3.2 billion DNA bases.
  • the reference genome an artificial genome composed by scientists, is the most common sequence of bases in human DNA. Genome of every individual differs from the reference genome by around 0.5% of bases, owing to genetic variations. These variations make each genotype unique and some of them can have significant impact on human health.
  • a standard procedure for obtaining individual variability is known.
  • collecting a biological sample is necessary (e.g. blood, saliva, etc.).
  • the DNA molecule is then extracted and prepared for a process called sequencing.
  • DNA sequencing is a biochemical process for determining the precise order of nucleotide bases within the DNA molecule.
  • the molecule When using the massive parallel sequencing technology, the molecule must be fragmented and placed on a sequencing platform. Here the fragments are read in parallel creating digital sequences of DNA bases called reads. These reads are randomly ordered with unknown direction and unknown DNA strand of origin.
  • genomic reads belong to an organism with a known reference genome, such as human, they can be sorted in the process called mapping. Aim of the mapping is to reconstruct the original genomic sequence. Each read is aligned and thus mapped to the most probable region of origin on the reference genome. An aligned and mapped read is often simply called alignment. Set of aligned reads is de facto a digital copy of the DNA contained within the biological sample.
  • genomic variants Aligned reads reveal differences between a sequenced and the reference genome, called genomic variants. Whole set or even specific selection of genomic variants is unique to each individual hence a genome is the ultimate person identifier. Although the majority of these variants have no apparent effect on an individual, genome-wide association studies have linked some of the variants to diseases, appearance or even the behavior of an individual.
  • Human genome is organized into 22 pairs of homologous chromosomes and one pair of sex chromosomes. In each pair, one chromosome is derived from the mother and the other one from the father.
  • the maternal and paternal chromosomes in a homologous pair have the same gene at the same locus, nevertheless alleles of this gene can differ between the chromosomes. If both alleles are identical, the organism is said to be homozygous forthat locus. If they differ, the organism is said to be heterozygous for that locus.
  • cffDNA cell-free fetal DNA
  • NIPS non-invasive prenatal screening
  • Fetal fraction as a proportion of fetal fragments in analyzed DNA mixture of mother's blood, is known to be affected by gestational age, maternal weight, placental size and function, whether the pregnancy is singleton or twin and also whether a trisomy is present [4-10] and other various factors (e.g. fetal crown-rump length, serum pregnancy- associated plasma protein-A, serum free P-human chorionic gonadotropin, hypertension, smoking, cancer [4,6,11-13],
  • cffDNA concentration of cffDNA in the maternal plasma must exceed 3-4% to provide a low false negative rate [22] but a low FF may also indicate a higher risk of aneuploidy [23,24], However, a higher FF is not always better.
  • An unusually elevated circulating levels of cffDNA have been reported in adverse pregnancy outcomes including preterm birth [25— 30], fetal growth restriction [31], gestational diabetes [32], preeclampsia [33-36], and abnormally invasive placenta [37], The underlying pathologies responsible for such quantitative changes has not been fully elucidated but has been suspected to be related to increased placental cell death or apoptosis [38]. Circulating fetal DNA levels may therefore be reflective of placental health, because cffDNA is thought to come from apoptotic placental trophoblastic cells [39],
  • cffDNA molecules are released into the bloodstream after cell death, they are mostly short in size less than 200 bp that show a fragmentation pattern resembling nuclease-cleaved nucleosomes; the distribution of molecules presents a succession of peaks, including a major 166-bp peak, a minor 143-bp peak and 10-bp periodic peaks below 143 bp.
  • the most significant difference in the size distribution between fetal and maternal DNA in maternal plasma is that fetal DNA exhibits a reduction in the 166-bp peak and an increased proportion of DNA molecules of less than 143 bp [40-42], This observation means that cffDNA has probably undergone more processing or metabolism than the bulk of the circulating maternal DNA molecules.
  • fetal fragments cannot be unambiguously distinguished from the maternal ones.
  • NIPT still does not achieve accuracy of invasive methods like amniocentesis, and further improvements are necessary for their full replacement.
  • sampling of genetic material from the mother’s circulation does not pose any direct risk for the fetus [48].
  • NGS next-generation sequencing
  • SNP quantification methods involve measuring the presence of reads containing single base pair mutations from the fetus [54-56]. Two main factors are the most important in calculating the FF in these methods: the number of SNPs used in the analysis [56]and read depth (to identify variants both for mother and for mixture of fetus-mother DNA) [57].
  • FetalQuant using high-depth sequencing data
  • FetalQuantSD using shallow-depth sequencing data
  • Count based methods calculate disproportion of the number of reads mapped to chromosomes between mother and fetus genotypes. Although they are quite reliable, they can be used only on samples with male (the number of DNA fragments matching the sequence of the Y chromosome should be directly proportionate to the FF) [20,60,61] or trisomic (2 copies vs. 3 copies of an aberrant chromosome) fetuses [62-64]. In pregnancy with a healthy female fetus, pregnancy has to be determined by alternative methods.
  • FL model is then based on the size analysis of short and long DNA fragments in the maternal plasma with the assumption that ratio of short DNA fragments and long DNA fragments is correlated to proportion of fetal DNA fragments in maternal plasma. For example in fetal trisomy 21 , the proportion of shorter reads would increase due to the extra chromosome copy. Conversely, in monosomy X the proportion of longer fragments of maternal origin increases. Dataset of measured values (read lengths distribution of each mother) is then divided into two groups: a training group and a validation group and together they are used to create a linear regression representing the resulting FF from read lengths distribution [65-67].
  • the SANEFALCON Single reAds Nucleosome-basEd FetAL fraCtiON method determines the fetal fraction through the distribution of reads mapped around nucleosome positions on autosomal chromosomes (independent of the fetal gender). Nucleosomedependent differences in degradation of maternal and fetal DNA lead to different start sites of sequence reads (i.e. fragment length). These changes correlate with the fetal fraction.
  • SANEFALCON uses a linear regression from the nucleosome profile to predict the fetal fraction, with coefficients learned from a training set [68].
  • the SeqFF method is a preferred method for samples with female fetus [20].
  • the basic principle involves discovering read overrepresentation in sub-chromosomal regions of 50 kbp.
  • the FF is then determined using standard multivariate regression models and is then the average of the predictions of the models. Estimation of these weights requires a huge amount of training samples that are scarcely available for small laboratories, and so the method is applicable only for established tests with a large cohort of pre-analyzed samples.
  • FF estimation method for determining whether genomic imbalance such as chromosomal aneuploidy exists within a biological sample based on a FF threshold.
  • the FF is computed from the same or different data used to determine the cut-off value.
  • the threshold value can be computed from the formula: (3XF+2X(1-F))/(2XF+2X(1 -F)), where F is the FF.
  • the method uses sites of genetic polymorphism where the mother is homozygous and the fetus is heterozygous.
  • FF is computed by comparison of the number of reads supporting the first allele and the number of reads supporting the second allele for a specific locus.
  • Telomeres are protective DNA-protein structures at the end of chromosomes that guard against genome degradation and inappropriate activation of DNA response [70,71]. They can serve as a potential indicator for disease susceptibility and cellular aging, predictors of mortality, or a possible target for a particular treatment [72].
  • TL is a dynamic marker that reflects not only genetic predispositions [88,89] but can be affected by individual's age [90], sex [91], hormones [92,93], exogenous life factors (e.g. stress [94], nutrition [95], exercise [96], obesity and weight loss [97], paternal age [98], alcohol dependence [99], tobacco smoking [100], socio-economic status [101]) and environmental exposures (e.g. air pollution [102], UV radiation [103]). It is closely related to longevity and a number of pathologies [104-106], such as cancer and cardiovascular diseases [107,108]. Therefore, TL at birth is a main predictor for TL throughout life [109- 111],
  • telomere shortening in offspring tissues through increases in maternally derived biological stress mediators during intrauterine life, or through alterations in parental behavior or care, which then affects offspring stress regulation and thereby induces changes in telomere biology [112].
  • telomere lengths in cord blood cells and placental cells shorten as gestation progresses, with the shortest telomeres being found at term. Consistent with the progressive loss of telomere DNA, placental and fetal membrane cells have been observed to have weak or no telomerase enzyme activity, especially during late gestation [117-119].
  • telomere length (TL) [109,120,121].
  • factors such as maternal stress [122,123], inflammation [124], gestational diabetes [125], exposure to air pollution [126,127], tobacco smoke [128], and toxic metals [129] may negatively influence offspring TL.
  • Telomeres may also be susceptible to poor or unbalanced nutrition [130].
  • Prepregnancy BMI has been found to be inversely associated with newborn TL [131]
  • maternal folate [120,132], vitamin C [133], and vitamin D [134] have been associated with longer telomeres in newborns.
  • NIPT The reliability of NIPT is dependent on a sufficient concentration of FF, which must exceed 3-4%.
  • FF fetal fraction
  • several methods have been developed for the estimation of the overall FF proportion based on aggregated characteristics of all sequenced fragments instead. These methods use various aspects of NGS technologies to determine the fetal fraction, e.g. Y chromosome-based DNA fragment estimation, fragment length distribution estimation methods, differential methylation methods, quantification of sSNPs and machine learning algorithms.
  • Our motivation is to develop new and independent FF estimation techniques based on telomere content estimation. The method can be used individually or in combination with alternative methods to achieve even higher precision.
  • Telomeres are structures at the end of chromosomes that protect the genome from degradation and they are composed of tandem repeats (10-15 kb at birth) of double-stranded DNA nucleotide sequence 5 -TTAGGG-3', and a final 3' G- rich single-stranded overhang (150-200 bp long) and shortens with age.
  • telomeres One notable feature of telomeres is their ability to shorten over time due to the gradual loss of nucleotide sequences with each cell division. This gradual shortening can contribute to cellular aging and senescence, which is a crucial factor in the development of age-related diseases.
  • the length of telomeres varies among different individuals and can be influenced by a range of factors, including genetics, environmental factors, and lifestyle choices. For example, research has shown that shorter telomeres are associated with a higher risk of chronic diseases such as cancer, cardiovascular disease, and diabetes.
  • the detection and characterization of the ongoing oncological disease is based on measuring the cell-free tumor DNA (cftDNA) fragments in the blood plasma of the patient.
  • cftDNA cell-free tumor DNA
  • the identification and quantification of tumor fragments is vital for the detection and characterization of ongoing oncology disease with application in its screening, monitoring and prognostics.
  • the genome of tumor tissue has typically different telomere length than healthy cells, the anomalies in the non-pregnant patient sample are indicative of on-going disease.
  • telomere length as a novel marker for FF estimation in NIPT.
  • telomere length in maternal blood could be used as a surrogate marker for FF estimation.
  • the method of the invention comprises steps on the level of biology (molecular biology) and bioinformatics (This invention does not rely on an exact method for obtaining sequencing and mapping data, therefore this gathering process is not described here in detail. However, people skilled in the field of molecular biology know how to get these data using one of the available technologies. Described in more detail in the example):
  • DNA The molecule inside cells that contains the genetic information responsible for the . development and function of an organism. DNA molecules allow this information to be passed from one generation to the next.
  • base pair (bp) A fundamental unit of DNA consisting of two nucleobases bound to each other by hydrogen bonds. genome The complete set of genes or genetic material present in a cell or organism, which contains all of the information needed for a person to develop and grow.
  • chromosome A structure found inside the nucleus of a cell. A chromosome is made up of proteins and DNA organized into genes. Each human cell normally contains 23 pairs of chromosomes. sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences.
  • DNA sequencing is the method that determines the order of the four nucleotides bases (adenine, thymine, cytosine, and guanine).
  • massive parallel sequencing technology/NGS A high-throughput method used to determine a portion of the nucleotide sequence of an individual’s genome. This technique utilizes DNA sequencing technologies that are capable of processing multiple DNA sequences in parallel. Also called next-generation sequencing and NGS.
  • telomere A region of repetitive DNA sequences at the end of a chromosome. Telomeres protect the ends of chromosomes from becoming frayed or tangled. Each time a cell divides, the telomeres become slightly shorter. Eventually, they become so short that the cell can no longer divide successfully, and the cell dies.
  • telomere length As a normal cellular process, a small portion of telomeric DNA is lost with each cell division. When telomere length reaches a critical limit, the cell undergoes senescence and/or apoptosis. Telomere length may therefore serve as a biological clock to determine the lifespan of a cell and an organism.
  • DNA-polymerase Enzyme that creates DNA molecules by assembling nucleotides, the building blocks of DNA. This enzyme is essential to DNA replication and usually works in pairs to create two identical DNA strands from one original DNA molecule.
  • telomerase The enzyme that repairs the telomeres of the chromosomes so that they do not become progressively shorter during successive rounds of chromosome replication. Telomerase activity is exhibited in gametes and stem and tumor cells.
  • cell division The division of a cell into two daughter cells with the same genetic material. Another name for cell division is "mitosis.”
  • apoptosis A type of cell death in which a series of molecular steps in a cell lead to its death. This is one method the body uses to get rid of unneeded or abnormal cells.
  • senescence A process by which a cell ages and permanently stops dividing but does not die. Overtime, large numbers of old (or senescent) cells can build up in tissues throughout the body. These cells remain active and can release harmful substances that may cause inflammation and damage to nearby healthy cells. Senescence may play a role in the development of cancer and other diseases.
  • mitochondria An organelle found in large numbers in most cells, in which the biochemical processes of respiration and energy production occur. Mitochondria contain their own small chromosomes. mitochondrial DNA (mtDNA) the small circular chromosome found inside mitochondria. Generally, mitochondria, and therefore mitochondrial DNA, are inherited only from the mother. oxidative stress An imbalance between free radicals and antioxidants in the body.
  • Free radicals are oxygen-containing molecules with an uneven number of electrons. The uneven number allows them to easily react with other molecules. Free radicals can cause large chain chemical reactions in the body because they react so easily with other molecules. When functioning properly, free radicals can help fight off pathogens. When there are more free radicals present than can be kept in balance by antioxidants, the free radicals can start doing damage to fatty tissue, DNA, and proteins, so that damage can lead to a vast number of diseases over time. Oxidative stress also contributes to aging. cancer A disease caused by an uncontrolled division of abnormal cells in a part of the body. Normally, human cells grow and multiply (through a process called cell division) to form new cells as the body needs them. When cells grow old or become damaged, they die, and new cells take their place.
  • somatic cells The cells in the body other than sperm and egg cells (which are called germ cells). In humans, somatic cells are diploid, meaning they contain two sets of chromosomes, one inherited from each parent.
  • genetic predisposition An increased chance or likelihood of developing a particular disease based on the presence of one or more genetic variants and/or a family history suggestive of an increased risk of the disease. Having a genetic predisposition does not mean an individual will develop the disease.
  • chromosome aberration A missing, extra, or irregular portion of chromosomal DNA - changes in chromosome number (gains and losses) and changes in structure (deletions, inversions, and exchanges). aneuploidy The presence of an abnormal number of chromosomes in a cell. An extra or missing chromosome is a common cause of some genetic disorders (also cancer). Aneuploidy originates during cell division when the chromosomes do not separate properly between the two cells (nondisjunction).
  • genetic marker A sequence of DNA with a known physical location on a chromosome. Genetic markers and genes that are close to each other on a chromosome tend to be inherited together. Genetic markers vary between individuals to the extent that they can be used to help find a nearby gene causing a certain disease or trait within a family.
  • genetic markers are single polymorphism nucleotides (SNPs), restriction fragment length polymorphisms (RFLPs), variable number of tandem repeats (VNTRs), microsatellites, and copy number variants (CNVs). Genetic markers may or may not have a known function.
  • SNPs single polymorphism nucleotides
  • RFLPs restriction fragment length polymorphisms
  • VNTRs variable number of tandem repeats
  • CNVs copy number variants
  • FASTQ file File containing all reads from a sequencer, together with its sequencing quality. This is the standard file format to store this data and it is usually compressed to save disk space. All the modern mapping software accept this format as input.
  • SAM/BAM file File that contains aligned sequencing reads in a text format (SAM) or a compressed binary format (BAM). For every read it contains its mapped position on the reference genome (if the mapping for that read was successful), the mapping quality, sequencing quality (if provided), the location of the paired read (in case of pair-end sequencing), and various other information. It is a standard for storing aligned reads. Each SAM/BAM file is dependent on the reference genome used - this information is stored in the header of the SAM/BAM file.
  • linear regression Linear model that assumes a linear relationship between the input variables and the single output variable and fits a linear equation to observed data. More specifically, the single output can be calculated from a linear combination of the input variables.
  • WGS Whole genome sequencing
  • telomerehunter takes a BAM file as input, extracts telomeric reads and sorts them into four different fractions (intratelomeric, junction spanning, subtelomeric and intrachromosomal) depending on their mapping position. Subsequently, the telomere content is calculated from the number of intratelomeric reads normalized by the total number of reads with a GC composition similar to that of telomeres.
  • Sequencing reads are aligned to the human reference genome (hg19). Subsequently, FASTQ files are mapped to human genome reference (preferably version GRCh38.p10), using Bowtie2 (v2.1.0) (Langmead and Salzberg, 2012) resulting in one Sequence Alignment Map (SAM) file for each sample. SAM files are converted to Binary Alignment Map (BAM) format, sorted and indexed using Samtools view, merge and index utilities (vO.1.19) (Li et al., 2009).
  • BAM Binary Alignment Map
  • Each BAM file consisting of mapped reads from a sample is processed using the Telomerehunter tool to determine the telomere content in a sample.
  • the Telomerehunter tool is used for estimating telomere content from human WGS data, whereas the telomere content is calculated as a number of intratelomeric reads per million reads with telomeric gc content.
  • having the telomere content values the prediction accuracy of existing methods for determination of the FF in a sample can be increased by incorporating telomere content into prediction models. Subsequently, the values of telomere content are used as an input variable in linear regression to predict the FF amount
  • Figure 1 The linear relationship between a telomere content and a FF in samples can be seen in Figure 1.
  • telomere content Having the values of telomere content the existing methods for determining the FF amount can be improved by adding the information about the quantity of telomere reads.
  • Statistical or machine learning methods suitable for regression problems are applied to the data consisting of FF amount calculated by existing algorithm and information about samples such as age of pregnant woman, gestational age, bmi index, telomere content and others to measure FFs.
  • Blood from pregnant women is collected. Blood plasma is separated after collection and prepared for DNA isolation. Standard fragment libraries for massively parallel sequencing are prepared (for example using Illumina NextSeq 500/550 High Output Kit v2 (San Diego, CA, USA).
  • Sequencing reads were aligned to the human reference genome (hg19). Subsequently, FASTQ files were mapped to human genome reference, version GRCh38.p10, using Bowtie2 (v2.1.0) (Langmead and Salzberg, 2012) resulting in one Sequence Alignment Map (SAM) file for each sample. SAM files were converted to Binary Alignment Map (BAM) format, sorted and indexed using Samtools view, merge and index utilities (vO.1.19) (Li et al., 2009).
  • BAM Binary Alignment Map
  • This device first maps reads from a sequenced sample to a human reference genome with Bowtie2 tool[135] which creates a BAM file representing aligned sequences.
  • a BAM file is further processed by the Telomerehunter tool to obtain the information about telomeres from the analyzed sample.
  • the Telomerehunter takes a BAM file as input, extracts and sorts telomeric reads and estimates the telomere content of the input sample, whereas GC biases are taken into account.
  • the telomere content which is calculated as the number of intratelomeric reads per million reads with telomeric gc content, is extracted from the results of the Telomerehunter tool.
  • the regression models are trained on the training data to predict a fetal fraction (FF) amount in a sample and their prediction accuracy is subsequently calculated from the testing data.
  • One of the models uses the telomere content for the FF prediction and the other model takes the telomere content and the SeqFF values as the independent variables of the multiple linear regression and calculates the FF as the outcome.
  • telomere length can influence other traits, such as maternal age.
  • relevant characteristics we collected relevant characteristics and combined them to create a predictive model that includes height, weight, DNA quantity, final sequencing library concentration, gestational age, maternal age, and BML
  • To train this model we divided our dataset into 80% for training (2050 samples) and 20% for testing (513 samples).
  • Using linear regression we trained the model to predict fetal fraction based on the informative characteristics (Fig. 2).
  • BioTech Basel 2021 , 10, doi:10.3390/biotech10030017.
  • Lister R.; Pelizzola, M.; Dowen, R.H.; Hawkins, R.D.; Hon, G.; Tonti-Filippini, J.; Nery, J.R.; Lee, L.; Ye, Z.; Ngo, Q.-M.; et al. Human DNA Methylomes at Base Resolution Show Widespread Epigenomic Differences. Nature 2009, 462, 315-322.
  • Telomere Shortening in Alcohol Dependence Roles of Alcohol and Acetaldehyde. J. Psychiatr. Res. 2019, 109, 27-32. Barragan, R.; Ortega-Azorin, C.; Sorli, J.V.; Asensio, E.M.; Coltell, O.; St-Onge, M.-P.; Portoles, O.; Corella, D. Effect of Physical Activity, Smoking, and Sleep on Telomere Length: A Systematic Review of Observational and Intervention Studies. J. Clin. Med. Res. 2021, 11, doi:10.3390/jcm11010076.

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Abstract

La présente invention concerne un procédé consistant à utiliser la longueur des télomères comme marqueur pour estimer la proportion des différents composants présents dans un mélange d'ADN, avec de larges applications dans le domaine des tests génétiques. Elle peut être utilisée comme technique indépendante ou complémentaire des procédés existants afin d'accroître la précision et la fiabilité des résultats. Dans le cadre des tests prénataux non invasifs (NIRT), le procédé peut fournir des informations précieuses sur la proportion d'ADN fœtal présent dans un échantillon sanguin maternel, ce qui permet d'identifier avec précision les troubles et les anomalies génétiques. Le procédé peut également s'appliquer à la détection et à la caractérisation d'une maladie oncologique existante, les anomalies au niveau de la longueur des télomères pouvant indiquer la présence de fragments d'ADN tumoral dans les échantillons de plasma sanguin.
PCT/SK2023/000005 2023-06-07 2023-06-07 Procédé d'estimation des proportions de mélanges d'adn acellulaire à partir de fragments issus des télomères Ceased WO2024253600A1 (fr)

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